Macrophage defense mechanisms against intracellular bacteria

In the paper

“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 Schaible, unpublished results).”

In the paper

“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 Schaible, unpublished data).”

In the paper

“Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not.”

In the paper

“This process involves the GTPases, Rac1, Rac2, and Cdc42.”

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

What the sources say

• Not checked yetcites [6] Cambier CJ Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids Nature 2014 505 218 222 24336213 PMC3961847 source

In the paper

“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)”

What the sources say

• Not checked yetcites [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 yetcites [12] Kant AM SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC Blood 2002 100 1852 1859 12176909 source

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“A hallmark of phagosome biogenesis is acidification of the phagosomal lumen by the proton pumping vATPase.”

In the paper

“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.”

In the paper

“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.”

In the paper

“The prime examples are alveolar MΦs, which keep the pulmonary surface under surveillance for inhaled pathogens.”

In the paper

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

In the paper

“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”

In the paper

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

In the paper

“Phagocytosis is a hallmark of anti-bacterial host defense.”

In the paper

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

In the paper

“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.”

In the paper

“At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells.”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [46] Bissig C Gruenberg J ALIX and the multivesicular endosome: ALIX in Wonderland Trends Cell Biol 2014 24 19 25 24287454 source

In the paper

“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.”

In the paper

“Some of those such as cathepsin D depend on further processing by other proteases and/or autocatalysis to generate the enzymatically active forms (40).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“This process can be blocked by calcineurin-inhibitors cyclosporin or FK506, resulting in reduction of mycobacterial proliferation within macrophages (20).”

What the sources say

• Not checked yetcites [20] Jayachandran R Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin Cell 2007 130 37 50 17632055 source

In the paper

“Lyso-biphosphatidic acids (LBPA) are key lipids of late endosomes/phagosomes and terminal phospholipid degradation products (44).”

What the sources say

• Not checked yetcites [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

In the paper

“Together, v- and t-SNARE establish a protein complex, which facilitates membrane fusion.”

In the paper

“Phagocytosis and fusion with the lysosomal azurophilic granules is often happening simultaneously.”

In the paper

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

In the paper

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

In the paper

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

In the paper

“The fusion between vesicles requires a closely adjacent position, which is facilitated by motor proteins.”

In the paper

“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).”

In the paper

“Removal of this actin ‘coat’ drives mycobacteria into phagolysosomes and limits mycobacterial growth.”

In the paper

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

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [32] Schaible UE Kaufmann SH Iron and microbial infection Nat Rev Microbiol 2004 2 946 953 15550940 source

In the paper

“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.”

In the paper

“These granules also deliver phagocytic receptors to the PMN surface for recognition and uptake of bacteria.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“At the same time, specific granules discharge iron sequestering lactoferrin and Lcn2 into both, the phagosomal lumen and the extracellular space.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [42] Winau F Saposin C is required for lipid presentation by human CD1b Nat Immunol 2004 5 169 174 14716313 source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [16] Yeung T Receptor activation alters inner surface potential during phagocytosis Science 2006 313 347 351 16857939 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [57] Bogdan C Nitric oxide and the immune response Nat Immunol 2001 2 907 916 11577346 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Non-degradable material is removed from the cell by exocytosis, i.e. outward budding of lysosome-derived vesicles.”

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“Activated MΦs can limit growth of intracellular bacteria including M. tuberculosis and drive phagosome maturation toward phagolysosomes and auto-phagolysosomes (54, 55).”

What the sources say

• Not checked yetcites [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 yetcites [55] Deretic V Saitoh T Akira S Autophagy in infection, inflammation and immunity Nat Rev Immunol 2013 13 722 737 24064518 PMC5340150 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [57] Bogdan C Nitric oxide and the immune response Nat Immunol 2001 2 907 916 11577346 source
• Not checked yetcites [58] Fang FC Antimicrobial reactive oxygen and nitrogen species: concepts and controversies Nat Rev Microbiol 2004 2 820 832 15378046 source
• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [89] Vromman F Subtil A Exploitation of host lipids by bacteria Curr Opin Microbiol 2014 17 38 45 24581691 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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)”

What the sources say

• Not checked yetcites [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

In the paper

“and the inhibition of FBA impairs M. tuberculosis proliferation and increases the susceptibility to mycobacteria to host responses (92).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [57] Bogdan C Nitric oxide and the immune response Nat Immunol 2001 2 907 916 11577346 source
• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [97] Zhang YJ Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing Cell 2013 155 1296 1308 24315099 PMC3902092 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [80] Stanley SA Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth PLoS Pathog 2014 10 e1003946 24586159 PMC3930586 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [114] Faurschou M Borregaard N Neutrophil granules and secretory vesicles in inflammation Microbes Infect 2003 5 1317 1327 14613775 source
• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [117] Brinkmann V Goosmann C Kuhn LI Zychlinsky A Automatic quantification of in vitro NET formation Front Immunol 2012 3 413 23316198 PMC3540390

In the paper

“Although MΦs killed by this cell death pathway are not efficiently phagocytosed by naive MΦs, this interaction still reduces the number of mycobacteria (154).”

What the sources say

• Not checked yetcites [154] Hartman ML Kornfeld H Interactions between naive and infected macrophages reduce Mycobacterium tuberculosis viability PLoS ONE 2011 6 e27972 22125644 PMC3220711 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [129] Erwig LP Henson PM Clearance of apoptotic cells by phagocytes Cell Death Differ 2008 15 243 250 17571081 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“It is well-established that increased availability of iron promotes the growth of M. tuberculosis and exacerbates TB (163–166).”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [166] Gangaidzo IT Association of pulmonary tuberculosis with increased dietary iron J Infect Dis 2001 184 936 939 11528590 source

In the paper

“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.”

What the sources say

• Not checked yetcites [178] Pantopoulos K Porwal SK Tartakoff A Devireddy L Mechanisms of mammalian iron homeostasis Biochemistry 2012 51 5705 5724 22703180 PMC3572738 source

In the paper

“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.”

In the paper

“Mice lacking NOS2 presented with MO iron loading, and intra-macrophage Salmonella were able to acquire more iron, which positively impacted on their proliferation.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [178] Pantopoulos K Porwal SK Tartakoff A Devireddy L Mechanisms of mammalian iron homeostasis Biochemistry 2012 51 5705 5724 22703180 PMC3572738 source

In the paper

“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”

What the sources say

• Not checked yetcites [170] Weiss G Schett G Anaemia in inflammatory rheumatic diseases Nat Rev Rheumatol 2013 9 205 215 23147894 source
• Not checked yetcites [171] Ganz T Nemeth E Hepcidin and disorders of iron metabolism Annu Rev Med 2011 62 347 360 20887198 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“In addition, IFN-γ further stimulates MO iron egress by this pathway and reduces the iron availability for intracellular bacteria (184).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [168] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 2013 13 509 519 23684303 PMC3676888 source
• Not checked yetcites [169] Drakesmith H Prentice AM Hepcidin and the iron-infection axis Science 2012 338 768 772 23139325 source
• Not checked yetcites [170] Weiss G Schett G Anaemia in inflammatory rheumatic diseases Nat Rev Rheumatol 2013 9 205 215 23147894 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [201] Pietrangelo A Hereditary hemochromatosis – a new look at an old disease N Engl J Med 2004 350 2383 2397 15175440 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“because mycobacterial ferritin expression is associated with resistance to oxidative stress and reduced susceptibility to antibiotics (177).”

What the sources say

• Not checked yetcites [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

In the paper

“Lcn2 has been shown to bind mycobacterial siderophores and to limit the growth of M. tuberculosis (210).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [169] Drakesmith H Prentice AM Hepcidin and the iron-infection axis Science 2012 338 768 772 23139325 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [212] Bao G Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex Nat Chem Biol 2010 6 602 609 20581821 PMC2907470 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [209] Jones CM Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling Proc Natl Acad Sci USA 2014 111 1945 1950 24497493 PMC3918798 source

In the paper

“Siderophores are synthesized and secreted by bacteria into their microenvironment to acquire soluble iron or to steal the metal from host iron proteins (205).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Thus, copper deficiency leads to iron overload and subsequent iron-mediated tissue damage.”

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“NRAMP1 is expressed in the late phagolysosome and has been characterized as a transporter for divalent metals and protons (221–225).”

What the sources say

• Not checked yetcites [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 yetcites [225] Cellier MF Nramp: from sequence to structure and mechanism of divalent metal import Curr Top Membr 2012 69 249 293 23046654 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Two of these proteins, S100A8 and S100A9, form a heterodimeric complex named calprotectin and are mainly expressed by PMN.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [233] Hood MI Skaar EP Nutritional immunity: transition metals at the pathogen-host interface Nat Rev Microbiol 2012 10 525 537 22796883 PMC3875331 source

In the paper

“In addition, Nramp1 expression increases Lcn2 formation, which contributes to the control of infection at least with intra-macrophage Salmonella (228).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [220] Blackwell JM Searle S Goswami T Miller EN Understanding the multiple functions of Nramp1 Microbes Infect 2000 2 317 321 10758409 source

In the paper

“The transition metal zinc plays central roles for the function of structural proteins and is essential for immune cell proliferation and differentiation (240).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say