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Cited by 991Tuberculosis Research and EpidemiologyImmune responses and vaccinationsImmune Response and Inflammation

Macrophage defense mechanisms against intracellular bacteria

Open access
Weiss, Günter, Schaible, Ulrich E.·2015·Immunological Reviews
DOI 10.1111/imr.12266PMC PMC4368383
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Abstract

Summary: Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis ( TB ), M ycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M . tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB ) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M . tuberculosis . These include induction of toxic anti‐microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti‐microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M . tuberculosis , as a prime example of a well‐adapted facultative intracellular bacterium, has learned during evolution to counter‐balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M . tuberculosis . Gaining more insights and knowledge into this complex network of host‐pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi‐resistance of M . tuberculosis against conventional antibiotics.

AI snapshot

Written from the paper’s full text.

TL;DR

This review describes how macrophages and neutrophils defend against intracellular bacteria, especially *Mycobacterium tuberculosis*, through phagosome maturation, radicals, autophagy, cytokines, efferocytosis, and nutrient/metal restriction. It also outlines *M. tuberculosis* counter-strategies and proposes host-pathogen interfaces as potential therapeutic targets.

Key findings

  • Macrophages use toxic effectors such as nitric oxide and reactive oxygen intermediates, phagolysosomal acidification, antimicrobial peptides and cytokines, autophagy, efferocytosis, and restriction of iron, fatty acids, amino acids, and other metals to contain intracellular bacteria.
  • *M. tuberculosis* counters these defenses by impairing phagosome maturation, resisting acidic and radical stress, manipulating host lipid metabolism, and securing iron via siderophores and other uptake pathways.
  • In human pulmonary tuberculosis, the review cites that 86% of patients were anemic and that anemic patients were three times more likely to have positive sputum smear results.
  • Iron availability promotes *M. tuberculosis* growth, while host iron-restriction pathways involving IFN-γ, ferroportin, Nramp1, lipocalin-2, and hepcidin can limit bacterial iron; in one cited mouse study, transgenic NRAMP1 expression reduced mycobacterial loads by one log in lung and spleen during the first 2 weeks after aerosol infection.

Methods

  • Narrative review; no primary experiments are reported.
  • Synthesizes mechanistic literature on macrophage and neutrophil innate immunity against intracellular bacteria, with a focus on *M. tuberculosis*.
  • Draws on in vitro, mouse, and human studies, including cited unpublished data, to describe host defense pathways and pathogen counter-strategies.

Limitations

  • The paper does not present a formal limitations section.
  • It notes that many mechanisms were demonstrated in mouse models or other intracellular bacteria such as *Salmonella typhimurium*, and whether they apply to *M. tuberculosis* remains to be shown.
  • Some cited findings rely on unpublished data; as a narrative review, no systematic search or quality appraisal is described.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/imr.12266

Cites

248 of 248 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 303 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The authors' recent finding indicates induction of necrosis, especially of PMNs, upon M. tuberculosis infection.

    “However, our recent finding on induction of necrosis, especially of PMNs, upon M. tuberculosis infection indicates analyses of this process are warranted.”
    Quote in the paperSubstantial claim
  • Findingown data

    M. tuberculosis growth in infected macrophages did not differ whether cells were deficient for hepcidin or hepcidin was added exogenously.

    “M. tuberculosis growth in infected MΦs did not differ, whether cells were deficient for hepcidin or it was added exogenously (M. Podinovskaya, P. Masaratana, RJ. Simpson, S. Vaulont, AT. McKie, UE. Schaible, unpublished results).”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Upon M. tuberculosis aerosol infection, NRAMP1-susceptible C57BL/6 mice complemented by transgenic functional NRAMP1 showed similar mycobacterial loads as susceptible littermates aside from the first 2 weeks, when transgenic mice had one log less mycobacteria in lung and spleen.

    “Upon M. tuberculosis aerosol infection, NRAMP1-susceptible C57BL/6 mice complemented by transgenic expression of a functional NRAMP1 gene showed similar mycobacterial loads as their susceptible littermates aside from the first 2 weeks after infection, when transgenic mice carrying a functional NRAMP1 had one log less mycobacteria in lung and spleen (M. Podinovskaya, P. Masaratana, RJ. Simpson, S.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Macrophage defense strategies include stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome.

    “the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome,”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The mycobacterial cord factor TDM delays phagosome maturation when coated onto beads.

    “Similarly, the mycobacterial cord factor TDM has been shown to delay phagosome maturation when coated onto beads (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Axelrod S Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide Cell Microbiol 2008 10 1530 1545 18363878 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 60
  • May combine two claims. 123

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The authors observed decoration of M. tuberculosis-infected PMNs by cathelicidin, suggesting that this AMP can contribute to PMN necrosis.

    “We observed decoration of M. tuberculosis-infected PMNs by cathelicidin, suggesting that this AMP can contribute to PMN necrosis (B. Corleis, UE. Schaible, unpublished results).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Hepcidin-deficient mice were as susceptible to aerosol infection with low dose M. tuberculosis as wildtype littermates, indicating that hepcidin-triggered changes in murine iron metabolism do not affect mycobacterial growth.

    “Of interest, hepcidin-deficient mice were as susceptible to aerosol infection with low dose M. tuberculosis, as wildtype littermates indicated that hepcidin-triggered changes in murine iron metabolism is not affecting mycobacterial growth (M. Podinovskaya, P. Masaratana, RJ. Simpson, S. Vaulont, AT. McKie, UE. Schaible, unpublished data).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The efficacy of phagocytes to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not.

    “Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Phagocytic cup formation involves the GTPases Rac1, Rac2, and Cdc42.

    “This process involves the GTPases, Rac1, Rac2, and Cdc42.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Toll-like receptors 1/2, 2/6, 4, 5, and 9 are specific for lipopeptides, lipopolysaccharides, flagellin, and low-methylated DNA sugar backbone, respectively, with TLR2/6 and 9 as pivotal PRRs for mycobacteria.

    “The Toll-like receptors (TLRs) 1/2, 2/6, 4, 5, and 9, are specific for lipopeptides, lipopolysaccharides, flagellin, and low-methylated DNA sugar backbone, respectively, with TLR2/6 and 9 as the pivotal PRRs for mycobacteria.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The stepwise succession of phagosomal maturation in macrophages is strikingly different from phagosome formation in PMNs.

    “The stepwise succession of phagosomal maturation in macrophages is strikingly different from phagosome formation in PMNs.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Macrophage defense strategies include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates.

    “These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates,”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases, which are delivered to the nascent phagosome bound to the M6PR from the trans-Golgi.

    “A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases, which are delivered to the nascent phagosome bound to the M6PR from the trans-Golgi.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Upon interaction of bacterial invaders with tissue macrophages and epithelial cells, initial inflammatory responses are triggered comprising secretion of cytokines, chemokines, small lipid mediators, and anti-microbial peptides.

    “Upon interaction of bacterial invaders with tissue MΦs and epithelial cells, initial inflammatory responses are triggered which comprises secretion of cytokines, chemokines, small lipid mediators (SLM) as well as anti-microbial peptides (AMPs).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Phenolic glycolipids promote recruitment of M. tuberculosis permissive macrophages via stimulation of host chemokine receptor 2 expression, whereas invasion of TLR-responsive microbicidal macrophages producing reactive nitrogen and oxygen species is impaired.

    “In addition, phenolic glycolipids promote the recruitment of M. tuberculosis permissive macrophages via stimulation of host chemokine receptor 2 expression, whereas the invasion of TLR responsive microbicidal macrophages producing reactive nitrogen and oxygen species is impaired (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Cambier CJ Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids Nature 2014 505 218 222 24336213 PMC3961847 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon ITAM phosphorylation, the SYK tyrosine kinase is recruited to the receptor and its activation leads to downstream phosphorylation events including activation of SHP-1 and RAC.

    “Upon ITAM phosphorylation, the SYK tyrosine kinase is recruited to the receptor and its activation leads to downstream phosphorylation events including activation of SHP-1 and RAC (11, 12)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Mocsai A Ruland J Tybulewicz VL The SYK tyrosine kinase: a crucial player in diverse biological functions Nat Rev Immunol 2010 10 387 402 20467426 PMC4782221 source

      Not checked in the free run.

    • cites [12] Kant AM SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC Blood 2002 100 1852 1859 12176909 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The fight of the host against the pathogen in M. tuberculosis infection involves several levels including containment of the microbe, generation of radicals and a hostile acidic environment, deprivation from essential nutrients, formation of anti-mycobacterial peptides and cytokines, and cell damage and suicidal activities of macrophages and PMNs such as autophagy, necroptosis, or efferocytosis to

    “the fight of the host against the pathogen in M. tuberculosis infection involves several levels including containment of the microbe, generation of radicals and a hostile, acidic environment, deprivation from essential nutrients, formation of anti-mycobacterial peptides and cytokines which strengthen host responses by attracting other immune cells, down to cell damage and suicidal activities of MO”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] Sambarey A Prashanthi K Chandra N Mining large-scale response networks reveals ‘topmost activities’ in Mycobacterium tuberculosis infection Sci Rep 2013 3 2302 23892477 PMC3725478 source

      Not checked in the free run.

    • cites [4] Bruns H Stenger S New insights into the interaction of Mycobacterium tuberculosis and human macrophages Future Microbiol 2014 9 327 341 24762307 source

      Not checked in the free run.

    • cites [5] Schnappinger D Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment J Exp Med 2003 198 693 704 12953091 PMC2194186 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Upon phagocytosis, epithelia-associated macrophages and dendritic cells carry engulfed bacteria to deeper tissues and further to draining lymph nodes.

    “Upon phagocytosis, epithelia-associated MΦs and other phagocytes such as dendritic cells (DCs) carry engulfed bacteria to deeper tissues and further to draining lymph nodes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Subsequent enclosure of the phagocytic cup leads to formation of the phagosome and initiates its biogenesis driven by fusion and fission events.

    “Subsequent enclosure of the phagocytic cup leads to formation of the phagosome and initiates its highly choreographed biogenesis driven by subsequent fusion and fission events.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Surface PRRs include C-type lectins, mannose receptor, dectin 1, dectin 2, Mincle, MCL, DC-SIGN, and scavenger receptors such as SR-A and MARCO, which recognize and bind bacteria to initiate phagocytosis.

    “Surface PRRs include C-type lectins, mannose receptor (MR), dectin 1, dectin 2, Mincle, MCL, DC-SIGN, and scavenger receptors such as SR-A and MARCO, which not only recognize but also bind bacteria to initiate phagocytosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including Mycobacterium tuberculosis, representing the forefront of innate immune defense against bacterial invaders.

    “Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Opsonized bacteria are bound by receptors for soluble PRR, C receptors (C1qR, CR3, CR4), and, in the presence of specific antibodies, Fcγ receptors (FcγR I-III).

    “Opsonized bacteria are subsequently bound by receptors for soluble PRR, C receptors (C1qR, CR3, CR4), and, in the presence of specific antibodies, Fcγ receptors (FcγR I-III).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In macrophages, the maturing phagosome traverses an early, late, and phagolysosomal stage paralleling endosomal maturation.

    “In MΦs, upon phagosome closure, the maturing phagosome traverses an early and late phagosomal and a phagolysosomal stage paralleling endosomal maturation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    STING is the receptor for cyclic GMP-AMP generated from microbial DNA, which is delivered into the cytoplasm by cGAMP synthase and triggers type 1 interferon production.

    “while STING is the recently described receptor for cyclic GMP-AMP generated from microbial DNA, which is delivered into the cytoplasm by cGAMP synthase, which triggers type 1 interferon production (1, 2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Watson RO Manzanillo PS Cox JS Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway Cell 2012 150 803 815 22901810 PMC3708656 source

      Not checked in the free run.

    • cites [2] Sun L Wu J Du F Chen X Chen ZJ Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway Science 2013 339 786 791 23258413 PMC3863629 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Acidification of the phagosomal lumen by the proton pumping vATPase is a hallmark of phagosome biogenesis.

    “A hallmark of phagosome biogenesis is acidification of the phagosomal lumen by the proton pumping vATPase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    IL-8 in humans (KC in mice), prostaglandins, and leukotrienes attract and/or activate PMNs, which perpetuate inflammation by secreting additional IL-8 and chemokines MCP-1, MIP1α/β, and IP10 that attract monocyte-derived macrophages and other immune cells.

    “Interleukin-8 (IL-8) in humans (KC in mice) as well as prostaglandins and leukotrienes attract and/or activate PMNs, which further perpetuate inflammation by secretion of additional IL-8 but also the chemokines MCP-1, MIP1α/β, and IP10 that attract monocyte-derived MΦs and other immune cells to the site of infection.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Upon binding and recognition of bacterial invaders, intracellular signaling pathways triggered by PRR, CR3, or FcRs induce actin polymerization and formation of the phagocytic cup.

    “Upon binding and recognition of bacterial invaders, intracellular signaling pathways triggered by PRR, CR3, or FcRs engaged by their respective ligands induce actin polymerization and formation of the phagocytic cup.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Alveolar macrophages keep the pulmonary surface under surveillance for inhaled pathogens.

    “The prime examples are alveolar MΦs, which keep the pulmonary surface under surveillance for inhaled pathogens.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the cytoplasm, NOD1, NOD2, and Galectin 3 sense DAP, muramyl-dipeptide, and β-galactosides, respectively.

    “In the cytoplasm, NOD1, NOD2, and Galectin 3 sense DAP, muramyl-dipeptide, and β-galactosides, respectively,”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    M. tuberculosis, as a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within the hostile environment.

    “M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Phagosome biogenesis is accompanied by continuous fusion and fission events, including fusion with trans-Golgi transport vesicles, endosomes, lysosomes, and autophagosomes.

    “Phagosome biogenesis is accompanied by continuous fusion and fission events, including fusion with trans-Golgi transport vesicles, endosomes, lysosomes, and autophagosomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Phagocytosis is a hallmark of anti-bacterial host defense.

    “Phagocytosis is a hallmark of anti-bacterial host defense.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Macrophages are in the center of infection with M. tuberculosis and other intracellular bacteria and use multiple strategies to eliminate these pathogens.

    “Macrophages are thus in the center of infection with M. tuberculosis and other intracellular bacteria and use multiple strategies to eliminate this pathogens.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisereasoning

    Downstream signaling cascades linked to these receptors induce receptor-mediated phagocytosis and pro-inflammatory responses executed by expression and/or secretion of chemokines and cytokines and release of anti-microbial effectors.

    “Downstream signaling cascades linked to these receptors induce receptor-mediated phagocytosis, a hallmark in host defense, in addition to a variety of pro-inflammatory responses executed by expression and/or secretion of chemokines and cytokines and release of anti-microbial effectors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Phagocytes are primary targets of intracellular bacteria to be abused as host cells.

    “At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Cdc42 can directly interact with WASP, which subsequently activates Arp2/3 as a direct initiator of actin polymerization.

    “The latter one can directly interact with WASP (Wiskott-Aldrich syndrome protein), which subsequently activates Arp2/3 as a direct initiator of actin polymerization.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Phagocytic cells such as macrophages and polymorphonuclear neutrophilic granulocytes represent the first line of defense against invading bacterial pathogens.

    “Phagocytic cells such as macrophages (MΦs) and polymorphonuclear neutrophilic granulocytes (PMNs) represent the first line of defense against invading bacterial pathogens.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Tissue-resident macrophages patrol epithelia of barrier organs, which are putative entry and colonization sites for pathogens and the first location for controlling infectious invaders.

    “tissue-resident MΦs patrol epithelia of barrier organs, which represent putative entry and colonization sites for pathogens and the first location for controlling infectious invaders.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In draining lymph nodes, antigens are presented to T cells by professional antigen-presenting cells such as dendritic cells and macrophages to initiate specific cellular immunity and generate specific T cells.

    “There, antigens are presented to T cells by professional antigen-presenting cells (APCs), such as DCs and MΦs (as well as B cells), to initiate specific cellular immunity and generate specific T cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis.

    “Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Mannose-capped lipoarabinomannan, phosphatidyl inositol mannosides, and trehalose dimycolate are mycobacterial ligands for MR, DC-SIGN, Mincle, and MCL, respectively.

    “Mannose-capped lipoarabinomannan (manLAM), phosphatidyl inositol mannosides (PIMs), as well as trehalose dimycolate (TDM) are mycobacterial ligands for MR, DC-SIGN, Mincle, and MCL, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Specific antibodies generated during a first encounter are essential for antigen-specific recognition and opsonization of a recurrent infectious agent and provide the basis of successful vaccines.

    “specific antibodies generated during the first encounter are essential for antigen-specific recognition and opsonization of a recurrent infectious agent, and provide the basis of successful vaccines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PDCD6IP binds in a Ca2+-dependent manner to endophilins, which influence endosomal membrane shape probably through interaction with dynamin via SH3 domains.

    “PDCD6IP also binds in a Ca2+-dependent manner to endophilins, which influence the endosomal membrane shape (bending) probably through interaction with dynamin via SH3 domains (46).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Bissig C Gruenberg J ALIX and the multivesicular endosome: ALIX in Wonderland Trends Cell Biol 2014 24 19 25 24287454 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Gelatinase granules spill out proteases and other enzymes to degrade extracellular matrix proteins, leading to tissue disruption to allow PMN evasion into the infection site but ultimately to pathogenesis.

    “Finally, the gelatinase granules spill out proteases and other enzymes to degrade extracellular matrix proteins, leading to tissue disruption to allow PMN evasion into infection site but ultimately to pathogenesis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some hydrolases such as cathepsin D depend on further processing by other proteases and/or autocatalysis to generate the enzymatically active forms.

    “Some of those such as cathepsin D depend on further processing by other proteases and/or autocatalysis to generate the enzymatically active forms (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Sturgill-Koszycki S Schaible UE Russell DG Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis EMBO J 1996 15 6960 6968 9003772 PMC452522 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The late phagosomal stage is characterized by acquisition of LAMP1 and 2 from endosomes as well as newly synthesized lysosomal enzymes delivered in trans-Golgi transport vesicles bound to M6PR, which are transiently enriched in late phagosomes.

    “The late phagosomal stage is characterized by the acquisition of the lysosome-associated membrane proteins (LAMP1 and 2) from endosomes as well as newly synthesized lysosomal enzymes delivered in trans-Golgi transport vesicles bound to the mannose-6-phosphate receptors (M6PR), which are transiently enriched in late phagosomes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Upon subsequent maturation, the late endosome-like phagosome is the transient stage toward an oxidative and hydrolytic compartment where phagosomal cargo is degraded, associated with loss of Rab5A and acquisition of Rab7A through the HOPS complex.

    “Upon subsequent maturation, the late endosome-like phagosome is the transient stage toward an oxidative and hydrolytic compartment, where the phagosomal cargo is degraded, and associated with the loss of Rab5A and acquisition of the late endosomal Rab7A through the HOPS (VpsC-homotypic protein sorting) complex.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inhibition of Abl tyrosine kinase by imatinib resulted in increased acidification of the lysosome and improved control of M. tuberculosis.

    “Inhibition of Abl tyrosine kinase by the clinically used drug imatinib resulted in increased acidification of the lysosome and improved control of M. tuberculosis (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Bruns H Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages J Immunol 2012 189 4069 4078 22988030 PMC3684563 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Calcineurin inhibitors cyclosporin or FK506 block this process, resulting in reduction of mycobacterial proliferation within macrophages.

    “This process can be blocked by calcineurin-inhibitors cyclosporin or FK506, resulting in reduction of mycobacterial proliferation within macrophages (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Jayachandran R Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin Cell 2007 130 37 50 17632055 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lyso-biphosphatidic acids are key lipids of late endosomes/phagosomes and terminal phospholipid degradation products.

    “Lyso-biphosphatidic acids (LBPA) are key lipids of late endosomes/phagosomes and terminal phospholipid degradation products (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Kobayashi T Stang E Fang KS de Moerloose P Parton RG Gruenberg J A lipid associated with the antiphospholipid syndrome regulates endosome structure and function Nature 1998 392 193 197 9515966 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Together, v- and t-SNARE establish a protein complex that facilitates membrane fusion.

    “Together, v- and t-SNARE establish a protein complex, which facilitates membrane fusion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In PMNs, phagocytosis and fusion with the lysosomal azurophilic granules often happen simultaneously.

    “Phagocytosis and fusion with the lysosomal azurophilic granules is often happening simultaneously.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The late endosome/phagosome is the intracellular compartment for membrane degradation.

    “The late endosome/phagosome is the intracellular compartment for membrane degradation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Rab11A is involved in recycling vesicles between the early endosome and plasma membrane, and probably also early phagosomes.

    “Rab11A is involved in recycling vesicles between the early endosome and plasma membrane, and probably also early phagosomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Inherited lack of saposins or pharmacological inhibition of certain lysosomal hydrolases leads to severe lysosomal storage diseases.

    “Inherited lack of saposins or pharmacological inhibition of certain lysosomal hydrolases leads to severe lysosomal storage diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Fusion between vesicles requires a closely adjacent position, which is facilitated by motor proteins.

    “The fusion between vesicles requires a closely adjacent position, which is facilitated by motor proteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    SNAREs are essential for vesicle fusion by forming fusogenic protein complexes at the cytoplasmic side of phagosomes comprising SNARE, NSF, and SNAP.

    “SNAREs are essential for vesicle fusion by forming fusogenic protein complexes at the cytoplasmic side of phagosomes comprising SNARE, NSF (N-ethylmaleimide sensitive factor), and SNAP (NSF-attachment protein).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Removal of the actin coat drives mycobacteria into phagolysosomes and limits mycobacterial growth.

    “Removal of this actin ‘coat’ drives mycobacteria into phagolysosomes and limits mycobacterial growth.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Scission of the newly formed phagosome from the plasma membrane seems to involve myosins.

    “Scission of the newly formed phagosome from the plasma membrane seems to involve myosins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The early endosome-like phagosome represents the first stage upon closure of the phagocytic cup.

    “The early endosome-like phagosome represents the first stage upon closure of the phagocytic cup.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Early phagosomes recruit Tf via TfR and have been suggested as an ideal niche for microbes that require iron for growth such as M. tuberculosis.

    “Early phagosomes recruit Tf via TfR and have therefore been suggested as an ideal niche for microbes, which require iron for growth such as M. tuberculosis (31, 32).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Halaas O Intracellular Mycobacterium avium intersect transferrin in the Rab11(+) recycling endocytic pathway and avoid lipocalin 2 trafficking to the lysosomal pathway J Infect Dis 2010 201 783 792 20121435 PMC2862295 source

      Not checked in the free run.

    • cites [32] Schaible UE Kaufmann SH Iron and microbial infection Nat Rev Microbiol 2004 2 946 953 15550940 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Fusion competence between two types of vesicles requires the presence of a vesicular SNARE on one and a target SNARE on the other vesicle.

    “Fusion competence between two types of vesicles requires the presence of a vesicular (v) on one and a target (t) SNARE on the other vesicle such as the VAMPs and syntaxins, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Specific granules deliver phagocytic receptors to the PMN surface for recognition and uptake of bacteria.

    “These granules also deliver phagocytic receptors to the PMN surface for recognition and uptake of bacteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lack of LPLA2 causes enhanced susceptibility to M. tuberculosis and S. typhimurium infection, although a direct microbicidal effect has not yet been found.

    “Its lack causes enhanced susceptibility to M. tuberculosis (43) and S. typhimurium infection (S. Renk, G. Graßl, P. Rausch, J. Shayman, BE. Schneider, UE. Schaible, unpublished data), although a direct microbicidal effect has not yet been found.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Schneider BE Behrends J Hagens K Harmel N Shayman JA Schaible UE Lysosomal phospholipase A2: a novel player in host immunity to Mycobacterium tuberculosis Eur J Immunol 2014 44 2394 2404 24825529 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Anti-bacterial activity has been described for a number of these hydrolases, which probably synergize with other microbicidal molecules such as defensins, cathelizidin, and ubiquitin-derived AMPs.

    “Anti-bacterial activity has been described for a number of these hydrolases, which probably synergize with other microbicidal molecules such as defensins, cathelizidin, and ubiquitin-derived AMPs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Specific granules discharge iron-sequestering lactoferrin and Lcn2 into both the phagosomal lumen and the extracellular space.

    “At the same time, specific granules discharge iron sequestering lactoferrin and Lcn2 into both, the phagosomal lumen and the extracellular space.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lysosomal lipid transfer proteins such as the four active saposins generated from pro-saposin by proteolytic cleavage are essential for glyco-lipid degradation and glyco-lipid homeostasis, in addition to their function in processing and presentation of lipid antigens by CD1b molecules in DC.

    “Lysosomal lipid transfer proteins (LTPs), such as the four active saposins generated from pro-saposin by proteolytic cleavage, are essential for glyco-lipid degradation in lysosomes and glyco-lipid homeostasis, in addition to their immunologically relevant function in processing and presentation of lipid antigens by CD1b molecules in DC (41, 42).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Kolter T Winau F Schaible UE Leippe M Sandhoff K Lipid-binding proteins in membrane digestion, antigen presentation, and antimicrobial defense J Biol Chem 2005 280 41125 41128 16230343 source

      Not checked in the free run.

    • cites [42] Winau F Saposin C is required for lipid presentation by human CD1b Nat Immunol 2004 5 169 174 14716313 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    This process is controlled by Abl tyrosine kinase, which negatively affects the expression of vATPase.

    “This process is controlled by Abl tyrosine kinase, which negatively affects the expression of vATPase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Phosphatidylinositide lipids synthesized by stage-specific phosphatidyl inositol kinases at the cytoplasmic sheet of phagosomal membranes are specific for different phagosome stages and functionally contribute to maturation-associated vesicle fusion and actin-polymerization associated processes.

    “In addition to stage-specific v-, t-SNAREs and Rab proteins, phosphatidylinositide (PI) lipids synthesized by stage-specific phosphatidyl inositol kinases (PIK) at the cytoplasmic sheet of phagosomal membranes are specific for different phagosome stages and functionally contribute to maturation-associated vesicle fusion and actin-polymerization associated processes (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Yeung T Receptor activation alters inner surface potential during phagocytosis Science 2006 313 347 351 16857939 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rab 3, 4, 5, 7, 9, 10, 11, and 14 are associated with pathogen-containing phagosomes and allocated to individual maturation stages.

    “A number of Rab proteins have been associated with pathogen-containing phagosomes including Rab 3, 4, 5, 7, 9, 10, 11, and 14 (14, 15) and allocated to individual maturation stages.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Galvez T Gilleron J Zerial M O'Sullivan GA SnapShot: Mammalian Rab proteins in endocytic trafficking Cell 2012 151 234 e2 23021225 source

      Not checked in the free run.

    • cites [15] Hoffmann C Functional analysis of novel Rab GTPases identified in the proteome of purified Legionella-containing vacuoles from macrophages Cell Microbiol 2014 16 1034 1052 24373249 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rab5A is a marker of early phagosomes and facilitates downstream maturation by recruiting EEA1, which then binds NSF, Rabex5, and Rabaptin-5 and subsequently syntaxin13 to form a fusogenic complex with endosomes.

    “The small GTPase Rab5A is a marker of early phagosomes and facilitates downstream maturation by recruiting early endosomal antigen 1 (EEA1), which then binds NSF, Rabex5, and Rabaptin-5 and subsequently syntaxin13 to form a fusogenic complex with endosomes (22–24).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] McBride HM Rybin V Murphy C Giner A Teasdale R Zerial M Oligomeric complexes link Rab5 effectors with NSF and drive membrane fusion via interactions between EEA1 and syntaxin 13 Cell 1999 98 377 386 10458612 source

      Not checked in the free run.

    • cites [23] Christoforidis S McBride HM Burgoyne RD Zerial M The Rab5 effector EEA1 is a core component of endosome docking Nature 1999 397 621 625 10050856 source

      Not checked in the free run.

    • cites [24] Lawe DC Sequential roles for phosphatidylinositol 3-phosphate and Rab5 in tethering and fusion of early endosomes via their interaction with EEA1 J Biol Chem 2002 277 8611 8617 11602609 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The early endosome recycles certain receptors back to the plasma membrane such as the TfR, which carries iron-loaded Tf to the early endosome, where Fe3+ is released for transfer to the cytoplasm.

    “The early endosome recycles certain receptors back to the plasma membrane such as the TfR, which carries iron-loaded Tf to the early endosome. There, it is released from the TfR to get rid of the two Fe3+ ions for transfer to the cytoplasm.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Using arginine and oxygen, the homodimeric NOS2 generates NO and citrulline, as one subunit transfers electrons between NADPH, FAD, flavin mononucleotide to the heme iron of the second subunit.

    “Using arginine and oxygen, the homodimeric NOS2 generates NO and citrulline, as one subunit transfers electrons between NADPH, FAD, flavin mononucleotide to the heme iron of the second subunit (56, 57).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Nathan C Shiloh MU Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens Proc Natl Acad Sci USA 2000 97 8841 8848 10922044 PMC34021 source

      Not checked in the free run.

    • cites [57] Bogdan C Nitric oxide and the immune response Nat Immunol 2001 2 907 916 11577346 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M. tuberculosis can survive at pH of 4.5, which has been linked to the expression of a specific resistance gene named Rv3671c.

    “However, M. tuberculosis can survive at pH of 4.5, which has been linked to the expression of a specific resistance gene named Rv3671c (47, 48).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Vandal OH Pierini LM Schnappinger D Nathan CF Ehrt S A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis Nat Med 2008 14 849 854 18641659 PMC2538620 source

      Not checked in the free run.

    • cites [48] Baker JJ Johnson BK Abramovitch RB Slow growth of Mycobacterium tuberculosis at acidic pH is regulated by phoPR and host-associated carbon sources Mol Microbiol 2014 94 56 69 24975990 PMC4177513 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    A number of bacterial infections induce lipid body formation including those by Chlamydia ssp., S. aureus, M. leprae, and M. tuberculosis, and foamy macrophages are found in infectious lesions.

    “A number of bacterial infections induce lipid body formation including those by Chlamydia ssp., S. aureus, M. leprae, and M. tuberculosis, and foamy MΦs are found in infectious lesions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Non-steroidal drugs including COX inhibitors (aspirin, ibuprofen) ameliorate PMN-driven necrotic granulomas and M. tuberculosis growth in mice but also abolish mycobacteria-induced lipid body formation and PGE2 production.

    “Consequently, non-steroidal drugs including COX inhibitors (aspirin, ibuprofen) ameliorate PMN-driven necrotic granulomas and M. tuberculosis growth in mice but also abolish mycobacteria-induced lipid body formation and PGE2 production (52, 53).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Vilaplana C Marzo E Tapia G Diaz J Garcia V Cardona PJ Ibuprofen therapy resulted in significantly decreased tissue bacillary loads and increased survival in a new murine experimental model of active tuberculosis J Infect Dis 2013 208 199 202 23564636 source

      Not checked in the free run.

    • cites [53] D'Avila H Melo RC Parreira GG Werneck-Barroso E Castro-Faria-Neto HC Bozza PT Mycobacterium bovis bacillus Calmette-Guerin induces TLR2-mediated formation of lipid bodies: intracellular domains for eicosanoid synthesis in vivo J Immunol 2006 176 3087 3097 16493068 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Non-degradable material is removed from the cell by exocytosis.

    “Non-degradable material is removed from the cell by exocytosis, i.e. outward budding of lysosome-derived vesicles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    NO must diffuse through the phagosomal membranes, since NOS2 is located at the cytoplasmic side of the phagosomal membrane.

    “NO must diffuse through the phagosomal membranes, since NOS2 is located at the cytoplasmic side of the phagosomal membrane.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Murine macrophages rely on IFN-γ plus PRR signals and/or TNF-α for full activation, whereas human monocyte-derived macrophages additionally require vitamin D2 as a cofactor, which facilitates expression of AMPs such as cathelicidin through binding to the vitamin D receptor.

    “Murine MΦs rely on IFN-γ plus PRR signals and/or TNF-α for full activation, whereas human MDMΦs additionally require vitamin D2 (VD) as a cofactor, which facilitates expression of AMPs such as cathelicidin (LL-37) through binding to the VD receptor (VDR).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Autophagy is further accelerated by microRNA-155, resulting in maturation of phagosomes and reduced survival of intracellular mycobacteria.

    “Autophagy is further accelerated by microRNA-155, resulting in maturation of phagosomes and reduced survival of intracellular mycobacteria.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Formation of lipid bodies requires the structural proteins perilipins 1-3, which are inserted in the body's rim.

    “Formation of lipid bodies requires the structural proteins, perilipins 1–3, which are inserted in the body's rim.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NOX2 consists of five catalytic subunits, which assemble after phagocytosis forming an active enzymatic complex producing superoxide anions and hydrogen peroxide along with the formation of hydroxyl radicals, the latter pathway being catalyzed by iron via the Fenton reaction.

    “NOX2 consists of five catalytic subunits, which assemble after phagocytosis thereby forming an active enzymatic complex producing superoxide anions and hydrogen peroxide along with the formation of hydroxyl radicals, the latter pathway being catalyzed by iron via the Fenton reaction (56, 59–61).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [56] Nathan C Shiloh MU Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens Proc Natl Acad Sci USA 2000 97 8841 8848 10922044 PMC34021 source

      Not checked in the free run.

    • cites [59] Klebanoff SJ Waltersdorph AM Michel BR Rosen H Oxygen-based free radical generation by ferrous ions and deferoxamine J Biol Chem 1989 264 19765 19771 2555330 source

      Not checked in the free run.

    • cites [60] Rosen GM Pou S Ramos CL Cohen MS Britigan BE Free radicals and phagocytic cells FASEB J 1995 9 200 209 7540156 source

      Not checked in the free run.

    • cites [61] Mastroeni P Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects on microbial proliferation and host survival in vivo J Exp Med 2000 192 237 248 10899910 PMC2193252 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The phagolysosome is the final product of late phagosome to lysosome fusion and is characterized by a pH of 4-4.5, high hydrolase activities, and low amounts of M6PR, LBPA, and PI(3)P.

    “The phagolysosome is the final product of late phagosome to lysosome fusion and is characterized by a pH of 4–4.5, high hydrolase activities and low amounts of M6PR, LBPA and PI(3)P.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    PGE2 and PMN influx can limit protective T-helper 1 cell responses and will therefore be beneficial for mycobacterial survival and growth.

    “PGE2 and PMN influx can limit protective T-helper 1 (Th1) cell responses and will therefore be beneficial for mycobacterial survival and growth.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The activated macrophage is better equipped with the antigen-presenting and co-stimulating molecules MHC I, II, CD80, and CD86 for T-cell activation, though not exceeding the optimal APC function of DCs.

    “The activated MO is also better equipped with the antigen-presenting and co-stimulating molecules MHC I, II, CD80, and CD86, respectively, for T-cell activation, though not exceeding the optimal APC function of DCs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Autophagy targets ubiquitinylated organelles/proteins to the autophagosome, which matures in similar steps as phagosomes and eventually fuses with lysosomes through recruitment of the SNARE syntaxin 17 to generate an auto-phagolysosome.

    “Autophagy targets ubiquitinylated organelles/proteins to the autophagosome, which matures in similar steps as phagosomes and eventually fuses with lysosomes through recruitment of the SNARE syntaxin 17 to generate an auto-phagolysosome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The activated macrophage has widely strengthened anti-bacterial capacities, including generation of reactive nitrogen intermediates such as nitric oxide through NOS2 and IDO-mediated tryptophan depletion through generation of N-formyl-kynurenine and its subsequent degradation products.

    “The activated MO has widely strengthened anti-bacterial capacities, including generation of reactive nitrogen intermediates such as nitric oxide (NO) through nitric oxide synthase activity (NOS2) and indoleamine 2,3-dioxygenase (IDO)-mediated tryptophan depletion through generation of N-formyl-kynurenine and its subsequent degradation products.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    T-cell activation in the context of pro-inflammatory cytokines such as IL-12, IL-18, and IL-23 secreted by macrophages and DCs leads to IFN-γ-producing Th1 cells and subsequent activation of macrophages and enhanced TNF-α secretion.

    “T-cell activation in the context of pro-inflammatory cytokines, such as IL-12, IL-18, and IL-23 secreted by MΦs and DCs, leads to interferon-γ (IFN-γ)-producing Th1 cells and subsequent activation of MΦs and enhanced TNF-α secretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Activated macrophages can limit growth of intracellular bacteria including M. tuberculosis and drive phagosome maturation toward phagolysosomes and auto-phagolysosomes.

    “Activated MΦs can limit growth of intracellular bacteria including M. tuberculosis and drive phagosome maturation toward phagolysosomes and auto-phagolysosomes (54, 55).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] Schneider BE A role for IL-18 in protective immunity against Mycobacterium tuberculosis Eur J Immunol 2010 40 396 405 19950174 PMC3189623 source

      Not checked in the free run.

    • cites [55] Deretic V Saitoh T Akira S Autophagy in infection, inflammation and immunity Nat Rev Immunol 2013 13 722 737 24064518 PMC5340150 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acidification of the phagolysosome decreases mycobacterial metabolism, which becomes highly dependent on the availability of specific carbon sources such as pyruvate, acetate, or cholesterol, otherwise resulting in growth arrest.

    “Of note, acidification of the phagolysosome decreases mycobacterial metabolism, which becomes highly dependent on the availability of specific carbon sources such as pyruvate, acetate, or cholesterol, otherwise resulting in growth arrest (48).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Baker JJ Johnson BK Abramovitch RB Slow growth of Mycobacterium tuberculosis at acidic pH is regulated by phoPR and host-associated carbon sources Mol Microbiol 2014 94 56 69 24975990 PMC4177513 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Highly reactive intermediates execute their microbicidal activity by oxidative destruction of membrane lipids, DNA, thiol and tyrosine residues, whereas NO can exert toxicity by directly targeting iron sulfur clusters of central metabolic enzymes.

    “Nonetheless, these highly reactive intermediates execute their microbicidal activity by oxidative destruction of membrane lipids, DNA, thiol and tyrosine residues, whereas NO can exert toxicity by directly targeting iron sulfur cluster of central metabolic enzymes (57, 58, 70–72).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [57] Bogdan C Nitric oxide and the immune response Nat Immunol 2001 2 907 916 11577346 source

      Not checked in the free run.

    • cites [58] Fang FC Antimicrobial reactive oxygen and nitrogen species: concepts and controversies Nat Rev Microbiol 2004 2 820 832 15378046 source

      Not checked in the free run.

    • cites [70] Nathan CF Hibbs JB Jr Role of nitric oxide synthesis in macrophage antimicrobial activity Curr Opin Immunol 1991 3 65 70 1711326 source

      Not checked in the free run.

    • cites [71] Weiss G Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway EMBO J 1993 12 3651 3657 7504627 PMC413641 source

      Not checked in the free run.

    • cites [72] MacMicking JD North RJ LaCourse R Mudgett JS Shah SK Nathan CF Identification of nitric oxide synthase as a protective locus against tuberculosis Proc Natl Acad Sci USA 1997 94 5243 5248 9144222 PMC24663 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M. tuberculosis reprograms the macrophage to exploit lipids derived from triacylglycerol and cholesterol, which accumulate in the bacteria-containing phagosome and lead to formation of foamy cell macrophages.

    “However, M. tuberculosis tries to reprogram the MO to exploit lipids derived from triacyclglycerol and cholesterol, which accumulate in the bacteria-containing phagosome and lead to the formation of foamy cell macrophages (89).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Vromman F Subtil A Exploitation of host lipids by bacteria Curr Opin Microbiol 2014 17 38 45 24581691 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDSC of the GR1intermediate/CD11b+ phenotype expressing IL-17 and arg1 accumulate at the rim of M. tuberculosis-induced lung granulomas, especially in the absence of NOS2, where they may be protective.

    “MDSC, as these cells are termed today, of the GR1intermediate/CD11b+ phenotype expressing IL-17 and arg1 accumulate at the rim of M. tuberculosis-induced lung granulomas, especially in the absence of NOS2, where they may be protective (111).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Obregon-Henao A Henao-Tamayo M Orme IM Ordway DJ Gr1(int)CD11b+ myeloid-derived suppressor cells in Mycobacterium tuberculosis infection PLoS ONE 2013 8 e80669 24224058 PMC3815237 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1β is massively induced upon infection of macrophages with M. tuberculosis and plays important roles in anti-mycobacterial immune defenses because knockout mice are more susceptible to this infection.

    “IL-1β is massively induced upon infection of macrophages with M. tuberculosis, and it appears to play important roles in anti-mycobacterial immune defenses because knockout mice are more susceptible to this infection (98)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Mayer-Barber KD Innate and adaptive interferons suppress IL-1alpha and IL-1beta production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection Immunity 2011 35 1023 1034 22195750 PMC3246221 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of FBA impairs M. tuberculosis proliferation and increases the susceptibility of mycobacteria to host responses.

    “and the inhibition of FBA impairs M. tuberculosis proliferation and increases the susceptibility to mycobacteria to host responses (92).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Puckett S Inactivation of fructose-1,6-bisphosphate aldolase prevents optimal co-catabolism of glycolytic and gluconeogenic carbon substrates in Mycobacterium tuberculosis PLoS Pathog 2014 10 e1004144 24851864 PMC4031216 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Breakdown products of fatty acids, such as propionyl-coenzyme A, can exert toxic effects toward mycobacteria, which detoxify this intermediate by converting it to acetyl-CoA for use as a central metabolic compound.

    “Of interest, breakdown products of fatty acids, such as propionyl–coenzyme A, can exert toxic effects toward mycobacteria, which thus try to detoxify this intermediate by converting it to acetyl-CoA that can be then used by bacteria as a central metabolic compound (91).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Lee W VanderVen BC Fahey RJ Russell DG Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress J Biol Chem 2013 288 6788 6800 23306194 PMC3591590 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Arg1 reduces the potential of activated macrophages to produce NO and generally limits tissue nitrogen sources important for T-cell activation and proliferation.

    “Thereby Arg1 reduces the potential of activated MΦs to produce NO and generally limits tissue nitrogen sources important for T-cell activation and proliferation (57, 107).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Bogdan C Nitric oxide and the immune response Nat Immunol 2001 2 907 916 11577346 source

      Not checked in the free run.

    • cites [107] Das P Lahiri A Lahiri A Chakravortty D Modulation of the arginase pathway in the context of microbial pathogenesis: a metabolic enzyme moonlighting as an immune modulator PLoS Pathog 2010 6 e1000899 20585552 PMC2887468 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    IFN-γ-inducible activation of IDO and subsequent reduction in tryptophan availability fails to exert an anti-mycobacterial effect because M. tuberculosis can synthesize tryptophan.

    “and thus IFN-γ-inducible activation of IDO and subsequent reduction in tryptophan availability fails to exert an anti-mycobacterial effect, whereas blockage of mycobacterial tryptophan synthesis increased the efficacy of this host defense mechanism (97).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Zhang YJ Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing Cell 2013 155 1296 1308 24315099 PMC3902092 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages from diabetic patients with low vitamin D2 levels have impaired control of M. tuberculosis infection ex vivo, which can be significantly augmented upon vitamin D supplementation.

    “Accordingly, macrophages from diabetic patients with low vitamin D2 levels were shown to have an impaired control of M. tuberculosis infection ex vivo, which can be significantly augmented upon vitamin D supplementation (86).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Lopez-Lopez N Vitamin D supplementation promotes macrophages' anti-mycobacterial activity in type 2 diabetes mellitus patients with low vitamin D receptor expression Microbes Infect 2014 16 755 761 25016144 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fluoxetine and gefitinib stimulate autophagy and reduce intra-macrophage survival of M. tuberculosis.

    “Specifically, fluoxetine, a selective serotoine re-uptake inhibitor, and gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) activity stimulated autophagy and reduced intra-macrophage survival of M. tuberculosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Stanley SA Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth PLoS Pathog 2014 10 e1003946 24586159 PMC3930586 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IDO deficient mice control M. tuberculosis infection as well as wildtype animals, and lack of IDO does not affect mycobacterial specific T-cell responses.

    “IDO deficient mice were able to control M. tuberculosis infection as good as wildtype animals and lack of IDO did not affect mycobacterial specific T-cell responses (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Blumenthal A M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection PLoS ONE 2012 7 e37314 22649518 PMC3359358 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the absence of functional NOS2, Arg1 exerts tissue protective effects and limits exacerbated granuloma formation and mycobacterial proliferation, traced to Arg1 controlling overwhelming T-cell activation.

    “Recent evidence also suggests that in the absence of functional NOS2, Arg1 exerts tissue protective effects and limits exacerbated granuloma formation and mycobacterial proliferation, which could be traced back to the function of Arg1 in controlling overwhelming T-cell activation (109).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Duque-Correa MA Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas Proc Natl Acad Sci USA 2014 111 E4024 E4032 25201986 PMC4183271 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Attenuated M. tuberculosis strains lacking the RD1 genomic virulence region extend the survival of PMNs before apoptotic suicide and are eventually killed in a ROI (MPO, NOX2)-dependent manner.

    “In contrast, attenuated M. tuberculosis strains lacking the RD1 genomic virulence region not only extend the survival of PMNs before apoptotic suicide but also eventually kills those attenuated strains in a ROI (MPO, NOX2)-dependent manner.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Corleis B Korbel D Wilson R Bylund J Chee R Schaible UE Escape of Mycobacterium tuberculosis from oxidative killing by neutrophils Cell Microbiol 2012 14 1109 1121 22405091 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Pyroptosis is a special case of necrosis, initiated by caspase-1, and leads to release of the pro-inflammatory cytokines IL-1β and IL-18.

    “Pyroptosis is a special case of necrosis, as it is initiated by caspase-1 and leads to release of the pro-inflammatory cytokines IL-1β and IL-18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Wang Q Imamura R Motani K Kushiyama H Nagata S Suda T Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages Int Immunol 2013 25 363 372 23446850 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PMNs carry three different types of granules: primary azurophilic, secondary specific, and tertiary gelatinase granules, which contain distinct anti-microbial effector molecules.

    “PMNs carry three different types of granules (Fig. 1): primary azurophilic, secondary specific, and tertiary gelatinase granules. These granules contain distinct anti-microbial effector molecules.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [114] Faurschou M Borregaard N Neutrophil granules and secretory vesicles in inflammation Microbes Infect 2003 5 1317 1327 14613775 source

      Not checked in the free run.

    • cites [115] McLeish KR Uriarte SM Tandon S Creed TM Le J Ward RA Exocytosis of neutrophil granule subsets and activation of prolyl isomerase 1 are required for respiratory burst priming J Innate Immun 2013 5 277 289 23363774 PMC3691856 source

      Not checked in the free run.

    • cites [116] Rorvig S Ostergaard O Heegaard NH Borregaard N Proteome profiling of human neutrophil granule subsets, secretory vesicles, and cell membrane: correlation with transcriptome profiling of neutrophil precursors J Leukoc Biol 2013 94 711 721 23650620 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The RD1 region of M. tuberculosis encodes the secretion apparatus ESX1 as well as secreted small proteins such as ESAT-6 and CFP-10.

    “The RD1 region of M. tuberculosis encodes the secretion apparatus ESX1 as well as secreted small proteins such as ESAT-6 and CFP-10.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Efferocytosis is the guarding mechanism to remove dying/dead cells from tissues during growth and remodeling, executed primarily by tissue macrophages and, upon onset of inflammation, by monocyte-derived macrophages as well as PMNs.

    “Efferocytosis is the guarding mechanism to remove dying/dead cells from tissues during growth and remodeling and is executed primarily by tissue MΦs and upon onset of inflammation by monocyte-derived MΦ as well as PMN.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In contrast to successive phagosome maturation in macrophages, which takes several minutes, phagosome maturation in PMNs is a matter of seconds and almost coincides with phagocytosis.

    “In contrast to the successive process of phagosome maturation in MΦs, which takes several minutes, it is a matter of seconds in PMNs. Actually, phagosome maturation is almost coinciding with phagocytosis, and fusion of preformed PMN granules happens during closure of the phagocytic cup.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Upon encountering microbes, PMNs release DNA forming neutrophil extracellular traps (NETs), which bind microbes and contribute to their killing.

    “Upon encountering microbes, PMNs release DNA forming NET (neutrophil extracellular traps), which bind microbes and contribute to their killing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Brinkmann V Goosmann C Kuhn LI Zychlinsky A Automatic quantification of in vitro NET formation Front Immunol 2012 3 413 23316198 PMC3540390

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although macrophages killed by this cell death pathway are not efficiently phagocytosed by naive macrophages, this interaction still reduces the number of mycobacteria.

    “Although MΦs killed by this cell death pathway are not efficiently phagocytosed by naive MΦs, this interaction still reduces the number of mycobacteria (154).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Hartman ML Kornfeld H Interactions between naive and infected macrophages reduce Mycobacterium tuberculosis viability PLoS ONE 2011 6 e27972 22125644 PMC3220711 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages comprise the first line of defense against M. tuberculosis by interacting with the pathogen at the primary site of infection, and neutrophils are recruited following macrophage apoptosis and eventual release of mycobacteria to the extracellular space.

    “Whereas macrophages comprise the first line of defense against M. tuberculosis by interacting with the pathogen at the primary site of infection, neutrophils are recruited following macrophage apoptosis and eventual release of mycobacteria to the extracellular space.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PMNs from chronic granulomatous disease patients lacking a functional NADPH-oxidase fail to succumb to necrotic cell death by wildtype M. tuberculosis but are also unable to kill attenuated strains.

    “Interestingly, PMNs from chronic granulomatous disease patients lacking a functional NADPH-oxidase fail to succumb to necrotic cell death by wildtype M. tuberculosis but are also unable to kill attenuated strains (120).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Corleis B Korbel D Wilson R Bylund J Chee R Schaible UE Escape of Mycobacterium tuberculosis from oxidative killing by neutrophils Cell Microbiol 2012 14 1109 1121 22405091 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Direct recognition of apoptotic material by efferocytes involves receptors including CR3, CR4, CD36, CD91, SR-A, vitronectin receptor, αvβ5 integrin, and Mincle, which also recognizes the M. tuberculosis cell wall lipid TDM.

    “For direct recognition of apoptotic material by efferocytes an array of receptors, which mediate tethering and/or engulfment, include CR3 and CR4, CD36, CD91 [low density lipoprotein receptor-related protein (LRP)], and other scavenging receptors (SR-A), vitronectin receptor (αvβ3) and αvβ5integrin as well as Mincle, which also recognizes the M. tuberculosis cell wall lipid TDM (134).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Richardson MB Williams SJ MCL and mincle: C-type lectin receptors that sense damaged self and pathogen-associated molecular patterns Front Immunol 2014 5 288 25002863 PMC4066366 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Efferocytosis enhances cholesterol efflux via the ATP-binding cassette transporters ABCA-1 and ABCG1 upon apoptosis (but not necrotic cell uptake), which protects efferocytes from cholesterol-induced ER stress and apoptosis upon massive uptake of dead cells.

    “Efferocytosis enhances cholesterol efflux via the ATP-binding cassette transporters A1 and G1 (ABCA-1, ABCG1) upon apoptosis (but not necrotic cell uptake), which protects efferocytes from cholesterol-induced ER stress and apoptosis upon massive uptake of dead cells (152, 153).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [152] Yvan-Charvet L ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis Circ Res 2010 106 1861 1869 20431058 PMC2995809 source

      Not checked in the free run.

    • cites [153] Cui D Pivotal advance: macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells J Leukoc Biol 2007 82 1040 1050 17576822 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Under homeostatic conditions, macrophages are the prime cells to clear out apoptotic bodies and remnants as well as necrotic material, and these cells are functionally termed efferocytes.

    “Under homeostatic conditions within the body, macrophages are the prime cells to clear out apoptotic bodies and remnants thereof as well as necrotic material. These cells are functionally termed efferocytes (129).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Erwig LP Henson PM Clearance of apoptotic cells by phagocytes Cell Death Differ 2008 15 243 250 17571081 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon co-culture with M. tuberculosis, PMNs actively migrate toward the mycobacteria in vitro and become activated upon phagocytosis, as indicated by ROI production, IL-8 release, and generation of active cathelicidin, MPO, and NETs.

    “Upon co-culture with M. tuberculosis, PMNs actively migrate toward the mycobacteria in an in vitro assay and become activated upon phagocytosis as indicated by ROI production, IL-8 release and generation of active cathelicidin, MPO and NETs (120).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Corleis B Korbel D Wilson R Bylund J Chee R Schaible UE Escape of Mycobacterium tuberculosis from oxidative killing by neutrophils Cell Microbiol 2012 14 1109 1121 22405091 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased availability of iron promotes the growth of M. tuberculosis and exacerbates TB.

    “It is well-established that increased availability of iron promotes the growth of M. tuberculosis and exacerbates TB (163–166).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [163] Schaible UE Collins HL Priem F Kaufmann SH Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis J Exp Med 2002 196 1507 1513 12461085 PMC2194267 source

      Not checked in the free run.

    • cites [164] Lounis N Truffot-Pernot C Grosset J Gordeuk VR Boelaert JR Iron and Mycobacterium tuberculosis infection J Clin Virol 2001 20 123 126 11166659 source

      Not checked in the free run.

    • cites [165] McDermid JM Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study BMC Infect Dis 2013 13 48 23360117 PMC3568026 source

      Not checked in the free run.

    • cites [166] Gangaidzo IT Association of pulmonary tuberculosis with increased dietary iron J Infect Dis 2001 184 936 939 11528590 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFN-γ induces transcription of ferritin and also affects its translation by modulating iron regulatory protein (IRP) binding affinity.

    “The Th1-derived cytokine IFN-γ induces the transcription but also affects the translation of the major iron storage protein ferritin, the latter being due to modulation of iron regulatory protein (IRP) binding affinity by the cytokine.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Pantopoulos K Porwal SK Tartakoff A Devireddy L Mechanisms of mammalian iron homeostasis Biochemistry 2012 51 5705 5724 22703180 PMC3572738 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The stimulation of hepcidin expression in the liver, a major mechanism for iron restriction to extracellular pathogens, is circumvented by mechanisms that remain elusive.

    “By mechanisms that remain elusive, the stimulation of hepcidin expression in the liver, which is a major mechanism for iron restriction to extracellular pathogens, is circumvented.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mice lacking NOS2 have macrophage iron loading, and intra-macrophage Salmonella acquire more iron, which positively impacts their proliferation.

    “Mice lacking NOS2 presented with MO iron loading, and intra-macrophage Salmonella were able to acquire more iron, which positively impacted on their proliferation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Nairz M Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection J Exp Med 2013 210 855 873 23630227 PMC3646493 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These events result in reduction in intracellular iron levels and limited availability of iron for intra-macrophage bacteria.

    “All these events result in reduction in intracellular iron levels and a limited availability of iron for intra-macrophage bacteria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Stimulation of ferroportin expression results in iron limitation to intra-macrophage bacteria and improved control of infection, also due to stimulation of macrophage effector functions as a consequence of intracellular iron deficiency.

    “Stimulation of ferroportin expression results in iron limitation to intra-macrophage bacteria and an improved control of the infection, which is also due to stimulation of MO effector functions as a consequence of intracellular iron deficiency.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [185] Nairz M Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection J Exp Med 2013 210 855 873 23630227 PMC3646493 source

      Not checked in the free run.

    • cites [187] Oexle H Pathways for the regulation of interferon-gamma-inducible genes by iron in human monocytic cells J Leukoc Biol 2003 74 287 294 12885946 source

      Not checked in the free run.

    • cites [188] Weiss G Werner-Felmayer G Werner ER Grunewald K Wachter H Hentze MW Iron regulates nitric oxide synthase activity by controlling nuclear transcription J Exp Med 1994 180 969 976 7520477 PMC2191642 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transcriptional analysis of macrophages and M. tuberculosis has demonstrated that mycobacteria regulate a myriad of genes to secure a sufficient supply of iron within the cell, whereas macrophages aim to restrict the availability of this metal by different mechanisms.

    “Accordingly, transcriptional analysis of macrophages and M. tuberculosis has demonstrated that Mycobacteria regulate a myriad of genes to secure a sufficient supply of iron within the cell, whereas macrophages aim to restrict the availability of this metal by different mechanisms (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Schnappinger D Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment J Exp Med 2003 198 693 704 12953091 PMC2194186 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The host immune system affects the metabolism and/or availability of metals for microbes via the action of cytokines, cellular proteins, or hormones, for which the term 'nutritional immunity' has been coined.

    “Thus, the host immune system affects the metabolism of these metals and/or their availability for microbes via the action of cytokines, cellular proteins, or hormones, for which the term ‘nutritional immunity’ has been coined.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The quick turnover of infected PMNs indicates that removal of dying/dead cells by efferocytes is important in TB but is either disturbed or cannot keep up with PMN influx, death, and bacterial growth.

    “The quick turnover of infected PMNs indicates that removal of dying/dead cells by efferocytes is important in TB but is either disturbed or cannot keep up with PMN influx, death, and bacterial growth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Activated macrophages express the phagolysosomal protein Nramp1, which pumps iron out of macrophages, reducing iron availability in the phagosome for mycobacteria.

    “Activated macrophages express the phagolysomal protein Nramp1, which among other effects pumps iron out of macrophages, thereby reducing the availability of the metal in the phagosome for mycobacteria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Iron retention in macrophages via the action of hepcidin and cytokines is a good strategy to limit the availability of the metal for circulating, extracellular pathogens, whereas it may be detrimental in the case of infection with an intracellular microbe such as M. tuberculosis.

    “Iron retention in MΦs via the action of hepcidin and cytokines is a good strategy to limit the availability of the metal for circulating, extracellular pathogens whereas it may be detrimental in case of an infection with a intracellular microbe, such as M. tuberculosis (161).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Nairz M Haschka D Demetz E Weiss G Iron at the interface of immunity and infection Front Pharmacol 2014 5 152 25076907 PMC4100575 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFN-γ stimulates NO formation, which activates IRP-1 binding to the ferritin IRE, leading to inhibition of ferritin translation.

    “IFN-γ stimulates NO formation, which then activates IRP-1 binding to the ferritin IRE, leading to inhibition of ferritin translation, whereas IRP-2 activity is affected depending on the type of cell and NO product (178).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Pantopoulos K Porwal SK Tartakoff A Devireddy L Mechanisms of mammalian iron homeostasis Biochemistry 2012 51 5705 5724 22703180 PMC3572738 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron restriction in monocytes and macrophages is achieved by the activity of cytokines such as TNF-α, IL-1, IL-6, and IL-10 on iron transport and storage proteins and by hepcidin, which binds ferroportin, resulting in its internalization and degradation, thereby blocking macrophage iron egress.

    “Iron restriction in monocytes and MΦs is achieved by the activity of different cytokines, such as TNF-α, IL-1, IL-6, and IL-10, on iron transport and storage proteins of macrophages and most importantly by the action of the liver-derived acute phase protein hepcidin, which binds to the only known cellular iron exporter ferroportin, resulting in its internalization and degradation, thereby blocking”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [170] Weiss G Schett G Anaemia in inflammatory rheumatic diseases Nat Rev Rheumatol 2013 9 205 215 23147894 source

      Not checked in the free run.

    • cites [171] Ganz T Nemeth E Hepcidin and disorders of iron metabolism Annu Rev Med 2011 62 347 360 20887198 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mycobacteria acquire iron through multiple avenues including acquisition from transferrin via the endocytic pathway, by directly binding iron-loaded transferrin via specific receptors, by uptake of cytoplasmic iron or heme iron by specific transporters, or by production of siderophores such as mycobactin.

    “Mycobacteria acquire iron through multiple avenues including the acquisition of the metal from transferrin via the endocytic pathway, by directly binding iron-loaded transferrin via specific receptors, by uptake of cytoplasmic iron or heme iron by specific transporters, or by the production of siderophores such as mycobactin, which can bind iron and re-utilize the metal (174–177).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [174] Olakanmi O Schlesinger LS Ahmed A Britigan BE Intraphagosomal Mycobacterium tuberculosis acquires iron from both extracellular transferrin and intracellular iron pools. Impact of interferon-gamma and hemochromatosis J Biol Chem 2002 277 49727 49734 12399453 source

      Not checked in the free run.

    • cites [175] Madigan CA Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis Proc Natl Acad Sci USA 2012 109 1257 1262 22232695 PMC3268331 source

      Not checked in the free run.

    • cites [176] Boradia VM Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin Nat Commun 2014 5 4730 25163484 source

      Not checked in the free run.

    • cites [177] Pandey R Rodriguez GM A ferritin mutant of Mycobacterium tuberculosis is highly susceptible to killing by antibiotics and is unable to establish a chronic infection in mice Infect Immun 2012 80 3650 3659 22802345 PMC3457556 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFN-γ further stimulates macrophage iron egress by the ferroportin pathway and reduces iron availability for intracellular bacteria.

    “In addition, IFN-γ further stimulates MO iron egress by this pathway and reduces the iron availability for intracellular bacteria (184).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Nairz M Fritsche G Brunner P Talasz H Hantke K Weiss G Interferon-gamma limits the availability of iron for intramacrophage Salmonella typhimurium Eur J Immunol 2008 38 1923 1936 18581323 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Induction of NOS2 expression and subsequent NO formation activates Nrf2, which stimulates ferroportin expression and induces iron export from macrophages.

    “Conversely, the induction of NOS2 expression and the subsequent formation of NO resulted in the activation of the transcription factor nuclear factor erythroid 2-related factor-2 (Nrf2), which stimulated the expression of ferroportin and induced iron export from macrophages (185) (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Nairz M Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection J Exp Med 2013 210 855 873 23630227 PMC3646493 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    IFN-γ directly inhibits TfR expression in monocytes, thereby decreasing iron concentration in the mycobacteria-containing phagosome.

    “The latter may be also referred to a direct inhibitory effect of IFN-γ on TfR expression in monocytes, thereby decreasing iron concentration in the mycobacteria containing phagosome (174, 181) (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [174] Olakanmi O Schlesinger LS Ahmed A Britigan BE Intraphagosomal Mycobacterium tuberculosis acquires iron from both extracellular transferrin and intracellular iron pools. Impact of interferon-gamma and hemochromatosis J Biol Chem 2002 277 49727 49734 12399453 source

      Not checked in the free run.

    • cites [181] Byrd TF Horwitz MA Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma J Clin Invest 1993 91 969 976 8450071 PMC288049 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alterations of iron traffic are thought to result from a defense strategy of the body to limit the availability of iron for invading pathogens, leading to retention of iron in macrophages and impaired iron absorption from the diet.

    “These alterations of iron traffic are thought to result from defense strategy of the body to limit the availability of iron for invading pathogens (167–169), which lead to retention of iron in MΦs and an impaired iron absorption from the diet (170).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [167] Nairz M Schroll A Sonnweber T Weiss G The struggle for iron – a metal at the host-pathogen interface Cell Microbiol 2010 12 1691 1702 20964797 source

      Not checked in the free run.

    • cites [168] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 2013 13 509 519 23684303 PMC3676888 source

      Not checked in the free run.

    • cites [169] Drakesmith H Prentice AM Hepcidin and the iron-infection axis Science 2012 338 768 772 23139325 source

      Not checked in the free run.

    • cites [170] Weiss G Schett G Anaemia in inflammatory rheumatic diseases Nat Rev Rheumatol 2013 9 205 215 23147894 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M. tuberculosis can stimulate hepcidin formation in macrophages and subvert ferroportin-mediated iron excess, ensuring iron retention within the macrophage.

    “However, M. tuberculosis can also stimulate the formation of hepcidin in MΦs and subvert the stimulation of ferroportin-mediated iron excess and ensure iron retention within the MO (197).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Sow FB Florence WC Satoskar AR Schlesinger LS Zwilling BS Lafuse WP Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis J Leukoc Biol 2007 82 934 945 17609338 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lcn2 formation is increased in macrophages infected with M. avium, and these bacteria avoid Lcn2-expressing phagosomes but reside within Rab11+ recycling endosomes, where they have access to transferrin.

    “Of interest, while Lcn2 formation is increased in macrophages infected with M. avium, these bacteria avoided population of Lcn2-expressing phagosomes but resided within Rab11+ recycling endosomes, where they have excess to transferrin (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Halaas O Intracellular Mycobacterium avium intersect transferrin in the Rab11(+) recycling endocytic pathway and avoid lipocalin 2 trafficking to the lysosomal pathway J Infect Dis 2010 201 783 792 20121435 PMC2862295 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ferroportin is found in the membrane of the M. tuberculosis-containing phagosome, which can be referred to a direct stimulatory effect of M. tuberculosis on ferroportin transcription.

    “Ferroportin was found in the membrane of the M. tuberculosis-containing phagosome, which can be referred to a direct stimulatory effect of M. tuberculosis on ferroportin transcription.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Van Zandt KE The iron export protein ferroportin 1 is differentially expressed in mouse macrophage populations and is present in the mycobacterial-containing phagosome J Leukoc Biol 2008 84 689 700 18586980 PMC2516892 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hfe−/− mice controlled invasive S. typhimurium infection significantly better than wildtype littermates, with reduced bacterial burden in spleen and liver and improved survival.

    “These mice were able to control invasive infection with S. typhimurium significantly better than wildtype littermates, which translated into reduced bacterial burden in spleen and liver and improved survival of Hfe−/− mice (204).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [204] Nairz M Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2 Blood 2009 114 3642 3651 19700664 PMC2766679 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The beneficial effect in Hfe−/− mice was linked to increased formation of Lcn2, and improved control of infection was abolished in Hfe−/− and Lcn2−/− double knockout mice.

    “This beneficial effect was linked to increased formation of lipocalin-2 (Lcn2) by Hfe−/− mice, whereas the improved control of infection was abolished in Hfe−/− and Lcn2−/− double knockout mice (204).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [204] Nairz M Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2 Blood 2009 114 3642 3651 19700664 PMC2766679 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In systemic M. avium infection, alterations of iron traffic were paralleled by increased expression of ferroportin whereas hepcidin formation in the liver remained unchanged.

    “This goes along with the observation in systemic M. avium infection demonstrating that alterations of iron traffic were paralleled by increased expression of ferroportin whereas hepcidin formation in the liver remained unchanged (200).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Rodrigues PN Mycobacteria-induced anaemia revisited: a molecular approach reveals the involvement of NRAMP1 and lipocalin-2, but not of hepcidin Immunobiology 2011 216 1127 1134 21601942 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic mutations affecting siderophore utilization by bacteria resulted in significant reduction in bacterial virulence or bacterial numbers in the lung and absent mortality in mice with tuberculosis.

    “Genetic mutations affecting siderophore utilization by the bacteria resulted in significant reduction in bacterial virulence or bacterial numbers in the lung and absent mortality in mice with tuberculosis (207, 208).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [207] Wells RM Discovery of a siderophore export system essential for virulence of Mycobacterium tuberculosis PLoS Pathog 2013 9 e1003120 23431276 PMC3561183 source

      Not checked in the free run.

    • cites [208] Reddy PV Disruption of mycobactin biosynthesis leads to attenuation of Mycobacterium tuberculosis for growth and virulence J Infect Dis 2013 208 1255 1265 23788726 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The HFE mutation leads to impaired formation of hepcidin and thus an iron deficiency phenotype of macrophages, whereas excessively absorbed iron is stored in parenchymal organs such as liver, heart, or pancreas.

    “The HFE mutation leads to an impaired formation of hepcidin and thus to an iron deficiency phenotype of MΦs, whereas excessively absorbed iron is stored in parenchymal organs such as the liver, heart, or pancreas.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201] Pietrangelo A Hereditary hemochromatosis – a new look at an old disease N Engl J Med 2004 350 2383 2397 15175440 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subjects with HFE-related hereditary hemochromatosis are more susceptible to infections with Yersinia spp. or Vibrio spp., but appear protected from infection with M. tuberculosis and S. typhimurium.

    “While subjects with HFE-related HH are more susceptible to infections with pathogens such as Yersinia spp. or Vibrio spp., they appear to be protected from infection with the intracellular bacteria M. tuberculosis and S. typhimurium (161, 202).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [161] Nairz M Haschka D Demetz E Weiss G Iron at the interface of immunity and infection Front Pharmacol 2014 5 152 25076907 PMC4100575 source

      Not checked in the free run.

    • cites [202] Silva-Gomes S Vale-Costa S Appelberg R Gomes MS Iron in intracellular infection: to provide or to deprive? Front Cell Infect Microbiol 2013 3 96 24367768 PMC3856365 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mycobacterial ferritin expression is associated with resistance to oxidative stress and reduced susceptibility to antibiotics.

    “because mycobacterial ferritin expression is associated with resistance to oxidative stress and reduced susceptibility to antibiotics (177).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Pandey R Rodriguez GM A ferritin mutant of Mycobacterium tuberculosis is highly susceptible to killing by antibiotics and is unable to establish a chronic infection in mice Infect Immun 2012 80 3650 3659 22802345 PMC3457556 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lcn2 binds mycobacterial siderophores and limits the growth of M. tuberculosis.

    “Lcn2 has been shown to bind mycobacterial siderophores and to limit the growth of M. tuberculosis (210).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [210] Holmes MA Paulsene W Jide X Ratledge C Strong RK Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration Structure 2005 13 29 41 15642259 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Poor outcome from tuberculosis may be linked to impaired lymphocyte proliferation with iron deficiency and impaired macrophage effector function with iron loading.

    “This outcome may be linked to impaired lymphocyte proliferation in association with iron deficiency and impaired macrophage effector function in association with iron loading (161, 169).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [161] Nairz M Haschka D Demetz E Weiss G Iron at the interface of immunity and infection Front Pharmacol 2014 5 152 25076907 PMC4100575 source

      Not checked in the free run.

    • cites [169] Drakesmith H Prentice AM Hepcidin and the iron-infection axis Science 2012 338 768 772 23139325 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NO modulates the IRE-binding function of IRPs, affecting ferritin translation and intracellular iron availability, linking maintenance of iron homeostasis to NO formation for host defense.

    “is part of a regulatory feedback loop, by which NO modulates the IRE-binding function of IRPs, thereby affecting ferritin translation and intracellular iron availability and linking maintenance of iron homeostasis to NO formation for host defense.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Lcn2 may contribute to limiting M. tuberculosis by shuttling iron out of macrophages, which is supposed to result from binding of a mammalian siderophore.

    “In addition, Lcn2 may contribute to this effect by shuttling iron out of macrophages, which is supposed to result from binding of a mammalian siderophore (211, 212).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [211] Devireddy LR Hart DO Goetz DH Green MR A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production Cell 2010 141 1006 1017 20550936 PMC2910436 source

      Not checked in the free run.

    • cites [212] Bao G Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex Nat Chem Biol 2010 6 602 609 20581821 PMC2907470 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Macrophages reduce synthesis of the siderophore 2,5-dihydroxybenzoic acid while increasing Lcn2 formation upon bacterial infection to limit microbial iron access.

    “Recent evidence suggests that macrophages reduce the synthesis of the siderophore 2,5-dihydroxybenzoic acid while increasing Lcn2 formation upon bacterial infection to limit microbial iron access (213), the relevance of this finding in M. tuberculosis infection remains to be shown.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [213] Liu Z Regulation of mammalian siderophore 2,5-DHBA in the innate immune response to infection J Exp Med 2014 211 1197 1213 24863067 PMC4042634 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M. tuberculosis recycles siderophores to enable efficient iron use, whereas disruption of this process results in iron-mediated self-poisoning of the bacteria.

    “Recent evidence suggest that M. tuberculosis recycle siderophores to enable efficient iron use, whereas disruption of this process results in iron-mediated self-poisoning of the bacteria (209).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Jones CM Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling Proc Natl Acad Sci USA 2014 111 1945 1950 24497493 PMC3918798 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Siderophores are synthesized and secreted by bacteria into their microenvironment to acquire soluble iron or to steal the metal from host iron proteins.

    “Siderophores are synthesized and secreted by bacteria into their microenvironment to acquire soluble iron or to steal the metal from host iron proteins (205).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [205] Chakraborty S Kaur S Guha S Batra SK The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer Biochim Biophys Acta 2012 1826 129 169 22513004 PMC3362670 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nramp1-mediated alterations of iron homeostasis stimulate anti-microbial immune effector function in murine macrophages, reflected by increased NO or TNF-α and significantly reduced IL-10.

    “In addition, Nramp1-mediated alterations of iron homeostasis stimulate anti-microbial immune effector function in murine macrophages as reflected by increased formation of NO or TNF-α whereas the expression of the anti-inflammatory cytokine IL-10 is significantly reduced (167, 190).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [167] Nairz M Schroll A Sonnweber T Weiss G The struggle for iron – a metal at the host-pathogen interface Cell Microbiol 2010 12 1691 1702 20964797 source

      Not checked in the free run.

    • cites [190] Fritsche G Nairz M Werner ER Barton HC Weiss G Nramp1-functionality increases iNOS expression via repression of IL-10 formation Eur J Immunol 2008 38 3060 3067 18991287 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Copper deficiency leads to iron overload and subsequent iron-mediated tissue damage.

    “Thus, copper deficiency leads to iron overload and subsequent iron-mediated tissue damage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    S100 proteins can be induced by IL-17 and IL-22, exert pro-inflammatory activity, and may promote chemotaxis of PMN.

    “In addition, S100 proteins can be induced by IL-17 and IL-22, and S100 proteins exert pro-inflammatory activity and may promote chemotaxis of PMN (233, 244).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [233] Hood MI Skaar EP Nutritional immunity: transition metals at the pathogen-host interface Nat Rev Microbiol 2012 10 525 537 22796883 PMC3875331 source

      Not checked in the free run.

    • cites [244] Diaz-Ochoa VE Jellbauer S Klaus S Raffatellu M Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis Front Cell Infect Microbiol 2014 4 2 24478990 PMC3900919 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NRAMP1 is expressed in the late phagolysosome and is a transporter for divalent metals and protons.

    “NRAMP1 is expressed in the late phagolysosome and has been characterized as a transporter for divalent metals and protons (221–225).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [221] Jabado N Jankowski A Dougaparsad S Picard V Grinstein S Gros P Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane J Exp Med 2000 192 1237 1248 11067873 PMC2193348 source

      Not checked in the free run.

    • cites [225] Cellier MF Nramp: from sequence to structure and mechanism of divalent metal import Curr Top Membr 2012 69 249 293 23046654 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DMT1 expression and iron transport capacity are increased in inflammatory macrophages.

    “DMT1 expression and iron transport capacity are increased in inflammatory MΦs (245); however, it has not been investigated whether this is also paralleled by increased accumulation of copper, zinc, or manganese in macrophages and whether or not this strengthens anti-microbial activities against M. tuberculosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [245] Ludwiczek S Aigner E Theurl I Weiss G Cytokine-mediated regulation of iron transport in human monocytic cells Blood 2003 101 4148 4154 12522003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pro-inflammatory cytokines such as IFN-γ induce expression of the copper permease Ctr1 in macrophages, resulting in increased uptake of copper into macrophages and translocation of P-type ATPase ATP7A to phagolysosomes, mediating copper influx and subsequent metal poisoning of bacteria.

    “Pro-inflammatory cytokines such as IFN-γ induce the expression of the copper permease Ctr1 in macrophages, which results in increased uptake of copper into macrophages and translocation of the P-type ATPase ATP7A to phagolysosomes, thereby mediating copper influx into these vesicles and subsequent metal poisoning of bacteria (236).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [236] White C Lee J Kambe T Fritsche K Petris MJ A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity J Biol Chem 2009 284 33949 33956 19808669 PMC2797165 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S100A8 and S100A9 form the heterodimeric complex calprotectin, which is mainly expressed by PMN.

    “Two of these proteins, S100A8 and S100A9, form a heterodimeric complex named calprotectin and are mainly expressed by PMN.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [233] Hood MI Skaar EP Nutritional immunity: transition metals at the pathogen-host interface Nat Rev Microbiol 2012 10 525 537 22796883 PMC3875331 source

      Not checked in the free run.

    • cites [244] Diaz-Ochoa VE Jellbauer S Klaus S Raffatellu M Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis Front Cell Infect Microbiol 2014 4 2 24478990 PMC3900919 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bacterial periplasmic superoxide-dismutases contain zinc or manganese to elaborate defense against host-mediated oxidative stress, and bacteria have a need for these metals.

    “Bacterial periplasmic superoxide-dismutases (SOD) contain zinc or manganese to elaborate their defense against host-mediated oxidative stress, and bacteria thus have a certain need for these metals (233).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Hood MI Skaar EP Nutritional immunity: transition metals at the pathogen-host interface Nat Rev Microbiol 2012 10 525 537 22796883 PMC3875331 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nramp1 expression increases Lcn2 formation, which contributes to the control of infection at least with intra-macrophage Salmonella.

    “In addition, Nramp1 expression increases Lcn2 formation, which contributes to the control of infection at least with intra-macrophage Salmonella (228).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Fritsche G Nairz M Libby SJ Fang FC Weiss G Slc11a1 (Nramp1) impairs growth of Salmonella enterica serovar typhimurium in macrophages via stimulation of lipocalin-2 expression J Leukoc Biol 2012 92 353 359 22706314 PMC3395419 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RAW264.7 macrophages expressing functional Nramp1 exhibited lower iron uptake via TfR and increased iron release via increased ferroportin expression, resulting in reduced cellular iron content.

    “Investigations of RAW264.7 MO cell line stably transfected with functional or non-functional Nramp1 demonstrated that MΦs expressing functional Nramp1 exhibited a lower iron uptake via TfR and an increased iron release mediated via increased ferroportin expression, resulting in reduced cellular iron content (228).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Fritsche G Nairz M Libby SJ Fang FC Weiss G Slc11a1 (Nramp1) impairs growth of Salmonella enterica serovar typhimurium in macrophages via stimulation of lipocalin-2 expression J Leukoc Biol 2012 92 353 359 22706314 PMC3395419 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron homeostasis and Lcn2 formation are linked to the activity of NRAMP1, which confers resistance to infections with intracellular pathogens such as Leishmania, Salmonella, or Mycobacteria.

    “Iron homeostasis and Lnc2 formation are also linked to the activity of natural resistance associated macrophage protein 1 (NRAMP1 or SLC11A1), conferring resistance to infections with intracellular pathogens, such as Leishmania, Salmonella, or Mycobacteria (219, 220).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [219] Forbes JR Gros P Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions Trends Microbiol 2001 9 397 403 11514223 source

      Not checked in the free run.

    • cites [220] Blackwell JM Searle S Goswami T Miller EN Understanding the multiple functions of Nramp1 Microbes Infect 2000 2 317 321 10758409 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Zinc plays central roles for the function of structural proteins and is essential for immune cell proliferation and differentiation.

    “The transition metal zinc plays central roles for the function of structural proteins and is essential for immune cell proliferation and differentiation (240).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Liu JZ Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut Cell Host Microbe 2012 11 227 239 22423963 PMC3308348 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Metal depletion strategies of the host affect pathogenic bacteria and commensal/protective flora, and bacteria that evolved strategies to outcompete metal restrictions benefit and may become more pathogenic.

    “However metal depletion strategies of the host not only affect pathogenic bacteria but also the commensal/protective flora, and thus bacteria that have evolved strategies to outcompete these metal restrictions benefit from a developmental advantage and may become more pathogenic (240).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Liu JZ Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut Cell Host Microbe 2012 11 227 239 22423963 PMC3308348 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Copper is a redox-active metal able to catalyze formation of toxic hydroxyl radicals, and copper accumulation is associated with increased anti-microbial toxicity also termed metal poisoning.

    “As with iron, copper is a redox-active metal able to catalyze the formation of toxic hydroxyl radicals, and copper accumulation is associated with increased anti-microbial toxicity also termed as metal poisoning (234).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [234] Samanovic MI Ding C Thiele DJ Darwin KH Copper in microbial pathogenesis: meddling with the metal Cell Host Microbe 2012 11 106 115 22341460 PMC3285254 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Copper plays important roles as a prosthetic group for many enzymes such as cytochromes, proteins involved in oxidative phosphorylation, or copper/zinc-superoxide dismutase.

    “In addition, copper plays important roles as a prostethic group for many enzymes such as cytochromes, proteins involved in oxidative phosphorylation or copper/zinc-superoxide dismutase (233).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Hood MI Skaar EP Nutritional immunity: transition metals at the pathogen-host interface Nat Rev Microbiol 2012 10 525 537 22796883 PMC3875331 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GM-CSF induced expression of two zinc transport proteins leading to accumulation of zinc in the Golgi apparatus, which triggered formation of toxic radicals by NADPH-oxidase and exerted anti-fungal activity against Histoplasma capsulatum.

    “Specifically, GM-CSF induced the expression of two zinc transport proteins leading to accumulation of the metal in the Golgi apparatus, which triggered the formation of toxic radicals by NADPH-oxidase and thereby exerting anti-fungal activity against Histoplasma capsulatum (241).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241] Subramanian Vignesh K Landero Figueroa JA Porollo A Caruso JA Deepe GS Jr Granulocyte macrophage-colony stimulating factor induced zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival Immunity 2013 39 697 710 24138881 PMC3841917 source

      Not checked in the free run.

162 of 162

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • TH1 cells produce IFN-γ, TNF, IL-2, GM-CSF and related cytokines which stimulate macrophages and neutrophils to kill intracellular but also extracellular bacteria.

    “T H 1 cells produce IFN-γ, TNF, IL-2, GM-CSF and related cytokines which stimulate macrophages and neutrophils to kill intracellular but also extracellular bacteria (Seder and Paul, 1994;Weiss and Schaible, 2015).”

    From Iron in infection and immunity (2020) · cites this paper as Weiss and Schaible, 2015

    The “Radical formation” section (page not provided) says Th1 cells produce IFN-γ, which activates macrophages and helps them limit intracellular bacteria. It does not establish the claimed Th1 production of IL-2 or GM-CSF, or that these cytokines stimulate neutrophils to kill extracellular bacteria. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Distinct amounts of iron are a prerequisite for sufficient translation of TNF and other cytokine messenger RNAs and for promotion of antimicrobial oxidative stress responses.

    “In contrast, distinct amounts of iron are a prerequisite for sufficient translation of TNF and other cytokine messenger RNAs (Wang et al., 2008) and promotion of antimicrobial oxidative stress responses (Vazquez-Torres et al., 2000;Weiss and Schaible, 2015).”

    From Iron in infection and immunity (2020) · cites this paper as Weiss and Schaible, 2015

  • Alongside O2•− production, macrophages employ direct antimicrobial mechanisms in the phagosome, such as reactive nitrogen species, cathepsins and other hydrolases.

    “Alongside O2•− production, macrophages employ several direct antimicrobial mechanisms in the phagosome, such as reactive nitrogen species RNS, as well as delivery of cathepsins and other hydrolases [201,202,203,204].”

    From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [203]

  • Macrophages employ direct antimicrobial mechanisms including generation of RNS in the phagosome and delivery of cathepsins and other hydrolases into maturing phagosomes.

    “Beyond the production of ROS, macrophages also employ an array of directly antimicrobial mechanisms, e.g., the generation of reactive nitrogen species (RNS) in the phagosome and the delivery of cathepsins and other hydrolases into maturing phagosomes [59,225,226,227,228,229,230].”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [226]

  • Macrophage iron metabolism and immune functions are interconnected.

    “Macrophage iron metabolism and immune functions are interconnected [57, 79, 165, 247].”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [247]

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Related

Authors
Weiss, G., & Schaible, U. E.
Affiliations
  • Innsbruck Medical University (AT)
  • London School of Hygiene & Tropical Medicine (GB)
Corresponding author
Weiss, Günter
ORCID
Venue
Immunological Reviews
Publisher
Wiley
Published
2015-02-20
Volume
264
Issue
1
Pages
182-203
ISSN
  • 0105-2896 (ISSN-L)
  • 1600-065X
DOI
10.1111/imr.12266
PMC
PMC4368383
OpenAlex
W2055224823
Cited by
989
References
251
Citations by year
2026: 67 · 2025: 80 · 2024: 107 · 2023: 112 · 2022: 112 · 2021: 106 · 2020: 91 · 2019: 103 · 2018: 72 · 2017: 72 · 2016: 48 · 2015: 18
FWCI
10.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunological Reviews (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Deutsches Zentrum für Infektionsforschung
  • Austrian Science Fund
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
macrophages, Mycobacterium tuberculosis, tuberculosis, innate immunity, intracellular bacteria, reactive oxygen species, nitric oxide, iron limitation, antimicrobial peptides, autophagy, efferocytosis, host-pathogen interaction, antibiotic resistance
MeSH terms
Animals, Cell Communication, Humans, Immunity, Innate, Lysosomes, Macrophage Activation, Macrophages, Metals, Mycobacterium tuberculosis, Phagocytes, Phagocytosis, Phagosomes, Tuberculosis, Host-Pathogen Interactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

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