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 Schaible, unpublished results).”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 Schaible, unpublished data).”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