Macrophage defense mechanisms against intracellular bacteria

In the paper

“Importantly, mycobacteria and TDM induced impairment of phagosome maturation can be overcome by IFN-γ (10).”

What the sources say

• Partly supported

  The paper reports that M. avium-containing phagosomes in murine macrophages advance toward a later stage of maturation after activation with IFN-γ and LPS (discussion and Figure 3; page unavailable). It does not address TDM-induced impairment, and its maturation experiments do not establish that IFN-γ alone overcomes the impairment. (LLM, conf=0.90)

  cites [10] Schaible UE Sturgill-Koszycki S Schlesinger PH Russell DG Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages J Immunol 1998 160 1290 1296 9570546 sourceExperimental — accuracy not yet measured

In the paper

“Of interest, recent evidence obtained in models of S. typhiumrium infection indicate specific compartmentalization of nitrosative and oxidative stress in macrophages and thus divergent effects on the fate and propagation of bacteria, extending previous work on cycle specific susceptibility of these bacteria to either of these stress responses (61, 68, 69).”

What the sources say

• Partly supported

  The Discussion (page not provided) reports divergent effects in experimental S. typhimurium infection: NADPH oxidase contributes to early bacterial killing, while iNOS is essential for later control of bacterial growth. It describes a temporal shift involving different phagocyte populations, but does not establish specific compartmentalization of oxidative and nitrosative stress within macrophages. (LLM, conf=0.86)

  cites [61] Mastroeni P Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects on microbial proliferation and host survival in vivo J Exp Med 2000 192 237 248 10899910 PMC2193252 sourceExperimental — accuracy not yet measured
• Partly supported

  In “Antibacterial actions of peritoneal macrophages from TLR4-deficient mice” (page not supplied), the paper distinguishes early oxidase-associated Salmonella killing from later, NO-dependent restriction of bacterial growth. That supports different effects on bacterial survival, but the passage describes differences over time, not specific compartmentalization of oxidative and nitrosative stress within macrophages. (LLM, conf=0.85)

  cites [68] Vazquez-Torres A Toll-like receptor 4 dependence of innate and adaptive immunity to Salmonella: importance of the Kupffer cell network J Immunol 2004 172 6202 6208 15128808 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion and the section ‘Local Nitrosative Stress Triggers Effective Salmonella Defense’ describe spatially varying oxidative and nitrosative stresses with different effects on Salmonella survival and spread during mouse infection. The claim’s restriction to stress compartmentalization ‘in macrophages’ is not supported: the paper locates lethal oxidative stress in neutrophils and inflammatory monocytes, sublethal oxidative bursts in resident macrophages, and nitrosative stress in regions of infected spleen. The indexed passages provide no page number. (LLM, conf=0.86)

  cites [69] Burton NA Disparate impact of oxidative host defenses determines the fate of Salmonella during systemic infection in mice Cell Host Microbe 2014 15 72 83 24439899 sourceExperimental — accuracy not yet measured

In the paper

“Killing of bacteria within this compartment has been attributed in part to ubiquitin-derived AMP generated by cathepsin D-mediated proteolysis (78).”

What the sources say

• Supported

  The Results and Discussion report bacterial killing after ubiquitin was preincubated with cathepsin D, among other lysosomal proteases, and attribute the activity to ubiquitin-derived peptides. The Conclusions identify these peptides as a potential killing mechanism in the autophagolysosome. The claim’s qualified wording is consistent with that evidence. (LLM, conf=0.88)

  cites [78] Alonso S Pethe K Russell DG Purdy GE Lysosomal killing of Mycobacterium mediated by ubiquitin-derived peptides is enhanced by autophagy Proc Natl Acad Sci USA 2007 104 6031 6036 17389386 PMC1851611 source

In the paper

“Similarly to IL-1β, IL-18 appears to be of importance to mount an efficient immune response because IL-18 knockout mice are more susceptible to M. tuberculosis infection than wildtype ones.”

What the sources say

• Supported

  The Discussion states that IL-18 knockout mice were highly susceptible to M. tuberculosis infection and succumbed more rapidly than wild-type mice. The Results also conclude that IL-18 is critically involved in protection against infection. (LLM, conf=0.95)

  cites [54] Schneider BE A role for IL-18 in protective immunity against Mycobacterium tuberculosis Eur J Immunol 2010 40 396 405 19950174 PMC3189623 source

In the paper

“These studies indicate that different MO populations are important to keep the tight balance between exacerbated pathology and control of bacterial growth.”

What the sources say

• Partly supported

  The Introduction and Results describe distinct Gr1+ myeloid-cell populations in tuberculosis-infected mice, rather than distinct macrophage populations. The Discussion links these cells to inflammation and possible tissue damage and increased bacterial burden, but says their role remains uncertain; it does not establish that they maintain the claimed balance between pathology and bacterial control. No page numbers are available in our copy. (LLM, conf=0.78)

  cites [111] Obregon-Henao A Henao-Tamayo M Orme IM Ordway DJ Gr1(int)CD11b+ myeloid-derived suppressor cells in Mycobacterium tuberculosis infection PLoS ONE 2013 8 e80669 24224058 PMC3815237 sourceExperimental — accuracy not yet measured

In the paper

“the enzyme heme oxygenase-1 (HO-1), which is induced in activated macrophages, exerts tissue protection by limiting the accumulation of pro-oxidant and cytotoxic heme molecules (104).”

What the sources say

• Supported

  The introduction (p. 1) says pathogen recognition by macrophages induces HO-1 and that HO-1 catabolizes free heme. The opening summary (p. 1) reports that, without HO-1, heme accumulates and acts as a cytotoxic pro-oxidant in infected macrophages; the Discussion (p. 9) likewise describes HO-1 preventing heme-induced cell death. (LLM, conf=0.92)

  cites [104] Silva-Gomes S Appelberg R Larsen R Soares MP Gomes MS Heme catabolism by heme oxygenase-1 confers host resistance to Mycobacterium infection Infect Immun 2013 81 2536 2545 23630967 PMC3697604 source

In the paper

“In another study however, apoptosis of infected MΦs and subsequent efferocytosis by naive ones have been described as efficient way to eliminate mycobacteria (155).”

What the sources say

• Supported

  The Abstract reports that uninfected macrophages engulf apoptotic M. tuberculosis-infected macrophages and that the bacteria are killed after efferocytosis. The Results section on control of Mtb growth also reports reduced bacterial recovery and, in some experiments, bacterial killing. Page numbers are not available in the supplied passages. (LLM, conf=0.93)

  cites [155] Martin CJ Efferocytosis is an innate antibacterial mechanism Cell Host Microbe 2012 12 289 300 22980326 PMC3517204 source

In the paper

“Moreover, hydrogen peroxide and superoxide anion modulate IRP-1 activity by a rapidly inducible process involving kinase/phosphatase signal transduction pathways resulting in divergent posttranscriptional regulation of IRE-regulated target genes such as transferrin receptor (TfR) and ferritin (178, 179).”

What the sources say

• Partly supported

  The Cellular iron storage section states that extracellular H2O2 inhibits ferritin mRNA translation through the IRE/IRP system. Cellular iron balance describes opposing posttranscriptional effects on TfR1 and ferritin. Neither passage establishes that superoxide modulates IRP1, that the response is rapid, or that kinase/phosphatase signaling mediates it; page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [178] Pantopoulos K Porwal SK Tartakoff A Devireddy L Mechanisms of mammalian iron homeostasis Biochemistry 2012 51 5705 5724 22703180 PMC3572738 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) links increased IRP2 activity in M2 macrophages to lower H-ferritin and higher TfR1 expression. The results section reports combined IRP1/IRP2 binding activity, but the paper does not establish that hydrogen peroxide or superoxide rapidly modulates IRP1 through kinase/phosphatase signaling. (LLM, conf=0.83)

  cites [179] Recalcati S Differential regulation of iron homeostasis during human macrophage polarized activation Eur J Immunol 2010 40 824 835 20039303 sourceExperimental — accuracy not yet measured

In the paper

“However, our recent finding on induction of necrosis, especially of PMNs, upon M. tuberculosis infection indicates analyses of this process are warranted.”

In the paper

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

In the paper

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

In the paper

“the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome,”

In the paper

“Similarly, the mycobacterial cord factor TDM has been shown to delay phagosome maturation when coated onto beads (9).”

What the sources say

• Not checked yetcites [9] Axelrod S Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide Cell Microbiol 2008 10 1530 1545 18363878 source

In the paper

“the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids,”

In the paper

“During this process, the maturing phagosome acquires and loses molecules functioning at but also characterizing individual maturation stages and diversion routes (7).”

What the sources say

• Not checked yetcites [7] Flannagan RS Cosio G Grinstein S Antimicrobial mechanisms of phagocytes and bacterial evasion strategies Nat Rev Microbiol 2009 7 355 366 19369951 source

In the paper

“Opsonization of invading bacteria is facilitated by soluble PRRs including surfactant proteins (SP-A, SP-D), and the mannose-binding lectin (MBL), as well as by the complement components C1q, C3, C3b, and C4.”

In the paper

“Once encountered, MΦs recognize bacteria via their microbe-associated molecular patterns (MAMPs) by surface exposed, vesicular, or cytoplasmic pattern recognition receptors (PRRs).”

In the paper

“However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions.”

In the paper

“FcγR-mediated phagocytosis accelerates phagosome maturation when compared to CR-mediated uptake,”

In the paper

“and engaging the MR for engulfment has even been associated with particle delivery into early phagosomes without immediate phagosome maturation.”

In the paper

“However, the receptors involved in uptake determine the speed by which a particle is delivered to the phagolysosome.”

In the paper

“the production of anti-microbial peptides and cytokines,”

In the paper

“and inhibition of SYK blocks phagosome maturation (13).”

What the sources say

• Not checked yetcites [13] Majeed M Caveggion E Lowell CA Berton G Role of Src kinases and Syk in Fcgamma receptor-mediated phagocytosis and phagosome-lysosome fusion J Leukoc Biol 2001 70 801 811 11698501 source

In the paper

“The phagosomal stages parallel those of endosomal maturation and can therefore be roughly divided into early (around 10 min after uptake) and late phagosomes (10–30 min) and phagolysosomes (later than 30 min).”

In the paper

“Of note, M. tuberculosis can evade immune recognition by macrophages upon masking their PRRs via cell surface-associated phthiocerol dimycocerosate (PDIM) lipids.”

In the paper

“Acceleration of phagosome maturation by engaging and clustering FcγR by antibody-opsonized bacteria is caused by Src-family kinase-mediated phosphorylation of the ITAM (immunoreceptor tyrosine-based activation motif) on the cytoplasmic part of the FcγR.”

In the paper

“along with induction of autophagy and efferocytosis to eliminate the pathogen.”

In the paper

“LTPs have been shown to have anti-microbial activity.”

In the paper

“Lysosomal phospholipase A2 (LPLA2) plays a unique role in degrading exogenous and endogenous membranes, including surfactant by alveolar MΦs as well as of engulfed bacteria.”

In the paper

“The early endosomal PI(3)P, which is synthesized by the PI3K VPS34, recruits proteins to the early endosome or phagosome essential for subsequent maturation.”

In the paper

“The PIs phosphatidyl inositol (4,5)-biphosphate [PI(4.5)P2] and PI(3,4,5)P3 participate in phagocytic cup formation and enclosure, probably in synergy with the SNAREs, VAMP3, and VAMP7, otherwise associated with recycling endosomes or exocytosis, respectively.”

In the paper

“The two latter ones require processing to their active components through proteolytic cleavage by PMN elastase, proteinase 3, or cathepsins, respectively (37, 38).”

What the sources say

• Not checked yetcites [37] Sorensen OE Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3 Blood 2001 97 3951 3959 11389039 source
• Not checked yetcites [38] Cole AM Shi J Ceccarelli A Kim YH Park A Ganz T Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds Blood 2001 97 297 304 11133774 source

In the paper

“M. tuberculosis phagosomes have also been described to acquire a coat protein, coronin or TACO.”

In the paper

“The enzymes delivered to late endosomes include cystein-, serine, and aspartate-proteases (such as the cathepsins B, L, and D), peptidases, glycosidases (such as N-acetylglycosaminidase, β-glucuronidase, β-galactosidase) as well as (phospho-) lipases.”

In the paper

“Consequently, vesicle fusion is essential for phagosome maturation.”

In the paper

“In this context, the Ca2+-binding synaptotagmin VII, which is linked to VAMP7 function in exocytosis, as well as the synaptotagmins II and XI have also been associated with phagosome formation and biogenesis including the link between phagosomes and lysosomes (17–19).”

What the sources say

• Not checked yetcites [17] Arango Duque G Fukuda M Descoteaux A Synaptotagmin XI regulates phagocytosis and cytokine secretion in macrophages J Immunol 2013 190 1737 1745 23303671 source
• Not checked yetcites [18] Lindmark IM Synaptotagmin II could confer Ca(2+) sensitivity to phagocytosis in human neutrophils Biochim Biophys Acta 2002 1590 159 166 12063179 source
• Not checked yetcites [19] Czibener C Ca2+ and synaptotagmin VII-dependent delivery of lysosomal membrane to nascent phagosomes J Cell Biol 2006 174 997 1007 16982801 PMC2064391 source

In the paper

“A hallmark of the late phagosome is its luminal acidification (pH of around 5) facilitated by the vATPase, which is assembled to function in the late phagosomal/endosomal membrane.”

In the paper

“The early phagosome lacks the proton pumping vesicular ATPase (vATPase) and is therefore characterized by a mildly acidic pH of 6–6.5 (21).”

What the sources say

• Not checked yetcites [21] Sturgill-Koszycki S Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase Science 1994 263 678 681 8303277 source

In the paper

“Coronin then activates the calcium-dependent phosphatase calcineurin, which inhibits phagosome-lysosome fusion (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

“LBPA is also functionally involved in membrane degradation by recruiting the programmed cell death-6-interacting protein (PDCD6IP) (45, 46).”

What the sources say

• Not checked yetcites [45] Matsuo H Role of LBPA and Alix in multivesicular liposome formation and endosome organization Science 2004 303 531 534 14739459 source
• 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

“Overexpression PDCD6IP promotes vacuolarization.”

In the paper

“For example, dynein and dynactin bring endosomes and phagosomes close together to promote fusion most probably involving the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, VAMP7, and VAMP8 (vesicle associated membrane proteins).”

In the paper

“Non-maturing M. tuberculosis phagosomes have been associated with actin nucleation by the multi-subunit complex, WASP, and SCAR homolog (WASH), which drives actin polymerization on endosomal membranes by activating the Arp2/3 complex (30).”

What the sources say

• Not checked yetcites [30] Kolonko M Geffken AC Blumer T Hagens K Schaible UE Hagedorn M WASH-driven actin polymerization is required for efficient mycobacterial phagosome maturation arrest Cell Microbiol 2014 16 232 246 24119059 source

In the paper

“This complex brings endosomes/phagosomes in close proximity as a prerequisite for fusion (probably involving VAMP7 and 8) (35, 36).”

What the sources say

• Not checked yetcites [35] Wade N Syntaxin 7 complexes with mouse Vps10p tail interactor 1b, syntaxin 6, vesicle-associated membrane protein (VAMP)8, and VAMP7 in b16 melanoma cells J Biol Chem 2001 276 19820 19827 11278762 source
• Not checked yetcites [36] Antonin W Holroyd C Tikkanen R Honing S Jahn R The R-SNARE endobrevin/VAMP-8 mediates homotypic fusion of early endosomes and late endosomes Mol Biol Cell 2000 11 3289 3298 11029036 PMC14992 source

In the paper

“PI(3)P also contributes to the recruitment of proteins containing PX or FYVE motifs including EEA1 and the NADPH-oxidase subunits p40phox and p47phox (25–27).”

What the sources say

• Not checked yetcites [25] Simonsen A EEA1 links PI(3)K function to Rab5 regulation of endosome fusion Nature 1998 394 494 498 9697774 source
• Not checked yetcites [26] Gaullier JM Simonsen A D'Arrigo A Bremnes B Stenmark H Aasland R FYVE fingers bind PtdIns(3)P Nature 1998 394 432 433 9697764 source
• Not checked yetcites [27] Kanai F The PX domains of p47phox and p40phox bind to lipid products of PI(3)K Nat Cell Biol 2001 3 675 678 11433300 source

In the paper

“Downstream effector proteins of Rab7A include the Rab-interacting lysosomal protein (RILP), which links the phagosomal membrane to a motor complex consisting of dynein and dynactin through stepwise recruitment of p150Glued, ORP1L, and the receptor βlll spectrin (33, 34).”

What the sources say

• Not checked yetcites [33] Johansson M Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-p150Glued, ORP1L, and the receptor betalll spectrin J Cell Biol 2007 176 459 471 17283181 PMC2063981 source
• Not checked yetcites [34] Jordens I The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors Curr Biol 2001 11 1680 1685 11696325 source

In the paper

“As the fusion process requires energy, GTPases, in this case of the Rab family, are also important for vesicle fusion during phagosome biogenesis.”

In the paper

“Incorporation of membranes into maturing endosomes/phagosomes requires an inward budding process.”

In the paper

“Acidification is required for the function of most lysosomal hydrolases with a low pH optimum.”

In the paper

“These observations point out modulation of SLM synthesis as a novel therapeutic strategy to accompany conventional antibiotic therapy in TB.”

In the paper

“Bacteria-containing phagosomes not only interact with vesicles of various origins during biogenesis but also with lipid storage compartments, i.e. lipid bodies (or droplets) (49).”

What the sources say

• Not checked yetcites [49] Melo RC Dvorak AM Lipid body-phagosome interaction in macrophages during infectious diseases: host defense or pathogen survival strategy? PLoS Pathog 2012 8 e1002729 22792061 PMC3390411 source

In the paper

“ESCORT proteins I and III have been shown to facilitate inward budding from phagosomal/endosomal membranes thereby generating multivesicular bodies (MVB).”

In the paper

“Infection-induced autophagy by IFN-γ activation or by starvation requires activation of the small GTPase LRG47 (IRGM in humans) (76, 77).”

What the sources say

• Not checked yetcites [76] Singh SB Davis AS Taylor GA Deretic V Human IRGM induces autophagy to eliminate intracellular mycobacteria Science 2006 313 1438 1441 16888103 source
• Not checked yetcites [77] Kim YM SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling Mol Cell 2012 46 833 846 22575674 PMC3389276 source

In the paper

“Upon stimulation with IFN-γ, macrophages activate GTPases, which are responsible for the recruitment of NOX2 to the mycobacterial phagosome (62, 63).”

What the sources say

• Not checked yetcites [62] Kim BH Shenoy AR Kumar P Das R Tiwari S MacMicking JD A family of IFN-gamma-inducible 65-kD GTPases protects against bacterial infection Science 2011 332 717 721 21551061 source
• Not checked yetcites [63] MacMicking JD Taylor GA McKinney JD Immune control of tuberculosis by IFN-gamma-inducible LRG-47 Science 2003 302 654 659 14576437 source

In the paper

“This process is controlled by beclin 1 (Atg6) complexed to the serine/threonine kinases ULK1, ULK2 (Atg1), as well as VPS34.”

In the paper

“Accordingly, Ass1-deficient macrophages fail to control mycobacterial infection (73).”

What the sources say

• Not checked yetcites [73] Qualls JE Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1 Cell Host Microbe 2012 12 313 323 22980328 PMC3444824 source

In the paper

“It has also been observed that both mutations or polymorphisms in the humans NOS2 or NOX2 genes are associated with an increased susceptibility to or a more severe course of tuberculosis (74, 75).”

What the sources say

• Not checked yetcites [74] Ehrt S Schnappinger D Mycobacterial survival strategies in the phagosome: defence against host stresses Cell Microbiol 2009 11 1170 1178 19438516 PMC3170014 source
• Not checked yetcites [75] Bustamante J Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease Nat Immunol 2011 12 213 221 21278736 PMC3097900 source

In the paper

“However, these compartments contain the enzymatic machinery including the arachidonic acid precursor for synthesis of eicosanoid SLM such as prostaglandins (PGs) and leukotrienes (LTs) involved in inflammation and PMN attraction.”

In the paper

“Although many of these observations originate from mouse models, the role of both RNI and ROI as central mediators of innate immune defense in human M. tuberculosis infection is well established.”

In the paper

“Limitation of L-arginine availability thus blocks NO formation.”

In the paper

“Access to lipid droplets allows phagosomal bacteria usage of TAG and other lipids as carbon sources.”

In the paper

“Both mycobacterial phagosomes and chlamydiophorous vacuoles interact with lipid bodies during bacterial dormancy (50, 51).”

What the sources say

• Not checked yetcites [50] Peyron P Foamy macrophages from tuberculous patients' granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence PLoS Pathog 2008 4 e1000204 19002241 PMC2575403 source
• Not checked yetcites [51] Cao C Laporte J Backer JM Wandinger-Ness A Stein MP Myotubularin lipid phosphatase binds the hVPS15/hVPS34 lipid kinase complex on endosomes Traffic 2007 8 1052 1067 17651088 source

In the paper

“However, excess TNF-α may have the opposite effect by inducing apoptosis and necrosis of infected macrophages via stimulation of receptor-interacting serine-threonine kinases 1 and 3 (RIP1 and RIP3) and excessive radical formation (64–66).”

What the sources say

• Not checked yetcites [64] He S Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha Cell 2009 137 1100 1111 19524512 source
• Not checked yetcites [65] Zhang DW RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis Science 2009 325 332 336 19498109 source
• Not checked yetcites [66] Cho YS Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation Cell 2009 137 1112 1123 19524513 PMC2727676 source

In the paper

“Autophagosomes are generated from PI(3)P carrying ER sheets (and other intracellular membranes including the Golgi) through recruitment of the lipid-binding proteins LC3A, LC3B, LC3C, and γ-aminobutyric acid receptor-associated proteins (Atg8).”

In the paper

“Therefore, the end product of the NO pathway, citrulline, has to be re-utilized to fuel arginine synthesis, which is managed by the enzymes arginine-succinate synthase (Ass1) and argininosuccinate lyase (Asl).”

In the paper

“In parallel, activated macrophages produce reactive oxygen intermediates (ROI) via activation of NOX2 (58).”

What the sources say

• Not checked yetcites [58] Fang FC Antimicrobial reactive oxygen and nitrogen species: concepts and controversies Nat Rev Microbiol 2004 2 820 832 15378046 source

In the paper

“In addition, macrophages can produce ROI by mitochondria in response to stimulation with TNF-α.”

In the paper

“However, to exert anti-bacterial activity by this pathway, NO has to be constantly produced.”

In the paper

“This results in release of mycobacteria into the extracellular medium, which promotes bacterial growth.”

In the paper

“After crossing the phagosomal membrane, NO and ROI can spontaneously react in the phagosomal lumen to generate nitrogen dioxide (NO2), peroxynitrite (ONOO−), dinitrogen trioxide (N2O3), nitrosothiols, nitroxyl (HNO), and dinitrosyl-iron complexes (58).”

What the sources say

• Not checked yetcites [58] Fang FC Antimicrobial reactive oxygen and nitrogen species: concepts and controversies Nat Rev Microbiol 2004 2 820 832 15378046 source

In the paper

“In a downstream conjugation cascade, the Atg5/Atg12/Atg16 complex supports linking LC3s to membrane phosphoethanolamine (55).”

What the sources say

• 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

“Activated macrophages can use macro-autophagy, the cellular intrinsic degradation and recycling system for senescent organelles and compartments, to eliminate intracellular bacteria such as L. monocytogenes, Shigella spp., and M. tuberculosis (55).”

What the sources say

• 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

“as well as to induction of autophagy (4, 85).”

What the sources say

• 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 [85] Jo EK Innate immunity to mycobacteria: vitamin D and autophagy Cell Microbiol 2010 12 1026 1035 20557314 source

In the paper

“whereas another Th17-derived cytokine, IL-22, exerts direct anti-mycobacterial activity in macrophages by stimulating phagolysosomal fusion.”

What the sources say

• Not checked yetcites [106] Dhiman R Venkatasubramanian S Paidipally P Barnes PF Tvinnereim A Vankayalapati R Interleukin 22 inhibits intracellular growth of Mycobacterium tuberculosis by enhancing calgranulin A expression J Infect Dis 2014 209 578 587 24041785 PMC3903372 source

In the paper

“Similarly, NO directly blocks inflammasome activation via nitrosylation of NLRP3, thereby preventing excessive tissue damage in the course of M. tuberculosis infection (102, 103).”

What the sources say

• Not checked yetcites [102] Hernandez-Cuellar E Cutting edge: nitric oxide inhibits the NLRP3 inflammasome J Immunol 2012 189 5113 5117 23100513 source
• Not checked yetcites [103] Mishra BB Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta Nat Immunol 2013 14 52 60 23160153 PMC3721324 source

In the paper

“The formation of IL-1β as well as of IL-18 from pro- IL-1β and pro-Il18β, respectively, is dependent on the activation of the inflammasome and of caspase-1 (100).”

What the sources say

• Not checked yetcites [100] Briken V Ahlbrand SE Shah S Mycobacterium tuberculosis and the host cell inflammasome: a complex relationship Front Cell Infect Microbiol 2013 3 62 24130966 PMC3793174 source

In the paper

“This results in increased expression of target genes containing vitamin D response elements within their promoter regions, such as the anti-microbial peptide cathelicidin (LL37) (83).”

What the sources say

• Not checked yetcites [83] Martineau AR IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37 J Immunol 2007 178 7190 7198 17513768 source

In the paper

“Therefore, it is no surprise that IFN-β transcriptome signatures were found to be associated with active but not latent TB (101).”

What the sources say

• Not checked yetcites [101] Berry MP An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis Nature 2010 466 973 977 20725040 PMC3492754 source

In the paper

“During M. tuberculosis infection inflammasome activation is controlled by the nucleotide binding and oligomerization domain, leucine rich-containing proteins 3 (NLRP3).”

What the sources say

• Not checked yetcites [100] Briken V Ahlbrand SE Shah S Mycobacterium tuberculosis and the host cell inflammasome: a complex relationship Front Cell Infect Microbiol 2013 3 62 24130966 PMC3793174 source

In the paper

“This is done by diversion of the host metabolism from a glycolytic pathway toward ketone biosynthesis, which is mediated by the mycobacterial virulence factor ESAT-6 (90).”

What the sources say

• Not checked yetcites [90] Singh V Jamwal S Jain R Verma P Gokhale R Rao KV Mycobacterium tuberculosis-driven targeted recalibration of macrophage lipid homeostasis promotes the foamy phenotype Cell Host Microbe 2012 12 669 681 23159056 source

In the paper

“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

“The expression of this latter receptor as well as the vitamin D converting hydroxylases, mainly vitamin D-1 hydroxylase CYP27b1, is induced after TLR2 activation of human monocytes/macrophages (82).”

What the sources say

• Not checked yetcites [82] Liu PT Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response Science 2006 311 1770 1773 16497887 source

In the paper

“Consequently, mice deficient in Arg1 are better protected against M. tuberculosis infection (108).”

What the sources say

• Not checked yetcites [108] El Kasmi KC Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens Nat Immunol 2008 9 1399 1406 18978793 PMC2584974 source

In the paper

“As a hallmark enzyme, alternatively activated MO express arginase 1 (Arg1) depleting the inflamed tissue of arginine by generating L-ornithine and urea, and the downstream products of ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT) activities, polyamines, and proline (important for induction of collagen deposits and fibrosis), respectively.”

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 human polymorphisms of IL-1 genes were associated with susceptibility to tuberculosis (99).”

What the sources say

• Not checked yetcites [99] Wilkinson RJ Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1beta on tuberculosis J Exp Med 1999 189 1863 1874 10377182 PMC2192963 source

In the paper

“M. tuberculosis is capable of reducing this activation pathway by inducing the formation of IFN-β, thereby contributing to immune evasion of the bacterium (100).”

What the sources say

• Not checked yetcites [100] Briken V Ahlbrand SE Shah S Mycobacterium tuberculosis and the host cell inflammasome: a complex relationship Front Cell Infect Microbiol 2013 3 62 24130966 PMC3793174 source

In the paper

“Several lines of evidence indicated that vitamin D metabolism plays an important role in human macrophage host responses to infection with mycobacteria.”

In the paper

“However, in the setting of M. tuberculosis infection, IDO activation appears to be ineffective in controlling the infection.”

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

“although recent data suggest that AMPK in association with PPARγ-coactivator1α strengthen anti-microbial immune effector mechanisms of infected macrophages by ameliorating mitochondrial function (94).”

What the sources say

• Not checked yetcites [94] Yang CS The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy Autophagy 2014 10 785 802 24598403 PMC5119058 source

In the paper

“On the other hand, IL-17 is important to mount a protective T cell-mediated immune response against M. tuberculosis (105)”

What the sources say

• Not checked yetcites [105] Chatterjee S Early secreted antigen ESAT-6 of Mycobacterium tuberculosis promotes protective T helper 17 cell responses in a toll-like receptor-2-dependent manner PLoS Pathog 2011 7 e1002378 22102818 PMC3213116 source

In the paper

“IDO induces the degradation of the essential amino acid tryptophan to kynurenine and subsequent breakdown products.”

In the paper

“TLR2 and TLR4 signals as well as vitamin D2 have been linked to induction autophagy as an anti-microbial effector mechanism (81).”

What the sources say

• Not checked yetcites [81] Medzhitov R Janeway CA Jr An ancient system of host defense Curr Opin Immunol 1998 10 12 15 9523104 source

In the paper

“Tryptophan is essential for M. tuberculosis growth, however, 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

“This effect is exerted upon binding of miR-155 to the 3′-untranslated region of RAS homolog enriched in brain (Rheb), which is a negative regulator of autophagy (79).”

What the sources say

• Not checked yetcites [79] Wang J MicroRNA-155 promotes autophagy to eliminate intracellular mycobacteria by targeting Rheb PLoS Pathog 2013 9 e1003697 24130493 PMC3795043 source

In the paper

“Another defense strategy to limit bacterial growth is amino acid deprivation by NOS2 and IDO upon MO activation (95).”

What the sources say

• Not checked yetcites [95] Schroecksnadel K Zangerle R Bellmann-Weiler R Garimorth K Weiss G Fuchs D Indoleamine-2, 3-dioxygenase and other interferon-gamma-mediated pathways in patients with human immunodeficiency virus infection Curr Drug Metab 2007 8 225 236 17430111 source

In the paper

“Alternatively activated MΦs are induced by a Th2 cell cytokine environment, i.e. IL-4 and IL-13.”

In the paper

“This effect could be traced back to IL-22-mediated activation of calgranulin A with subsequent induction of Rab7 and inhibition of Rab14 expression (106).”

What the sources say

• Not checked yetcites [106] Dhiman R Venkatasubramanian S Paidipally P Barnes PF Tvinnereim A Vankayalapati R Interleukin 22 inhibits intracellular growth of Mycobacterium tuberculosis by enhancing calgranulin A expression J Infect Dis 2014 209 578 587 24041785 PMC3903372 source

In the paper

“Part of the anti-mycobacterial activity of cathelicidin can be traced back to augmentation of NOX2-mediated ROI formation and modulation of cytokine expression (84)”

What the sources say

• Not checked yetcites [84] Sonawane A Cathelicidin is involved in the intracellular killing of mycobacteria in macrophages Cell Microbiol 2011 13 1601 1617 21790937 source

In the paper

“That points to the importance of modulating the availability of nutrients to pathogens as part of the host response (88).”

What the sources say

• Not checked yetcites [88] Ehrt S Rhee K Mycobacterium tuberculosis metabolism and host interaction: mysteries and paradoxes Curr Top Microbiol Immunol 2013 374 163 188 23242856

In the paper

“The effect of gefitinib could be traced back to blockade of EGFR mediated p38-MAPK activation, a known inhibitory pathway of autophagy (80).”

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

“By inhibiting peroxisome proliferator-activated receptor γ (PPARγ), vitamin D prevented M. tuberculosis-induced lipid droplet accumulation, which is essential for mycobacterial multiplication (87).”

What the sources say

• Not checked yetcites [87] Salamon H Cutting edge: vitamin D regulates lipid metabolism in Mycobacterium tuberculosis infection J Immunol 2014 193 30 34 24899504 PMC4073889 source

In the paper

“In terms of glucose consumption, the enzyme fructose-1,6-bisphosphanate aldolase (FBA) is essential for mycobacteria to get access to carbon sources derived from carbohydrates, 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

“These observations could be recently traced back to the fact that M. tuberculosis is able to synthesize tryptophan, and thus IFN-γ-inducible activation of IDO and subsequent reduction in tryptophan availability fails to exert an anti-mycobacterial effect, whereas blockage of mycobacterial tryptophan synthesis increased the efficacy of this host defense mechanism (97).”

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

“Efferosomes containing apoptotic material follow a similar succession as phagosomes going from an early to late endosomal to phagolysosomal stages as indicated by differential association with marker proteins such as the small GTPases Rab5 and Rab7, Vsp34 and dynamin, Lamp-1, and finally lysosomal hydrolases (136) (Fig. 1).”

What the sources say

• Not checked yetcites [136] Kinchen JM A pathway for phagosome maturation during engulfment of apoptotic cells Nat Cell Biol 2008 10 556 566 18425118 PMC2851549 source

In the paper

“Apoptotic cells release ‘find me’ and expose ‘eat me’ signals such as PS, lysoPS, cardiolipin, calreticulin, and CD31, as well as the chemokine fractalkine (CX3CL1 as recognized by CX3CR1) and small amounts of nucleotides (ATP, UTP). These ligands are recognized by phagocytes promoting efferocytosis (131, 132).”

What the sources say

• Not checked yetcites [131] Fullard JF Kale A Baker NE Clearance of apoptotic corpses Apoptosis 2009 14 1029 1037 19291407 source
• Not checked yetcites [132] Poon IK Lucas CD Rossi AG Ravichandran KS Apoptotic cell clearance: basic biology and therapeutic potential Nat Rev Immunol 2014 14 166 180 24481336 PMC4040260 source

In the paper

“PMNs are of importance in containment of mycobacteria following their release from apoptotic/necrotic macrophages (118, 119).”

What the sources say

• Not checked yetcites [118] Eum SY Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB Chest 2010 137 122 128 19749004 PMC2803122 source
• Not checked yetcites [119] Lowe DM Redford PS Wilkinson RJ O'Garra A Martineau AR Neutrophils in tuberculosis: friend or foe? Trends Immunol 2012 33 14 25 22094048 source

In the paper

“The aim of these neutrophils is to take up such mycobacteria and to rapidly kill them (112).”

What the sources say

• Not checked yetcites [112] Yang CT Cambier CJ Davis JM Hall CJ Crosier PS Ramakrishnan L Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages Cell Host Microbe 2012 12 301 312 22980327 PMC3638950 source

In the paper

“As reported previously, apoptotic blebs from infected MΦs can also promote cross presentation and protective T-cell immunity (137, 157).”

What the sources say

• Not checked yetcites [137] Winau F Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis Immunity 2006 24 105 117 16413927 source
• Not checked yetcites [157] Schaible UE Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis Nat Med 2003 9 1039 1046 12872166 source

In the paper

“PMNs are essential to take over the job when massive cell death occurs (130).”

What the sources say

• Not checked yetcites [130] Rydell-Tormanen K Uller L Erjefalt JS Neutrophil cannibalism – a back up when the macrophage clearance system is insufficient Respir Res 2006 7 143 17166290 PMC1716176 source

In the paper

“In contrast, virulent M. tuberculosis avoids MO apoptosis by inhibiting annexin I cross-linking and membrane repair, which ultimately leads to necrosis (123).”

What the sources say

• Not checked yetcites [123] Gan H Lee J Ren F Chen M Kornfeld H Remold HG Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence Nat Immunol 2008 9 1189 1197 18794848 PMC5351782 source

In the paper

“An inflammatory environment can also hinder efferocytosis of apoptotic corpses limited by TLR4 signals and TNF-α (139–141).”

What the sources say

• Not checked yetcites [139] Borges VM TNFalpha inhibits apoptotic cell clearance in the lung, exacerbating acute inflammation Am J Physiol Lung Cell Mol Physiol 2009 297 L586 L595 19648283 PMC2770785 source
• Not checked yetcites [140] Fernandez-Boyanapalli R Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-gamma in a nitric oxide-dependent manner J Immunol 2010 185 4030 4041 20805415 PMC4346245 source
• Not checked yetcites [141] Shiratsuchi A Watanabe I Takeuchi O Akira S Nakanishi Y Inhibitory effect of Toll-like receptor 4 on fusion between phagosomes and endosomes/lysosomes in macrophages J Immunol 2004 172 2039 2047 14764668 source