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Host Innate Immune Response to Mycobacterium tuberculosis

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This review focuses on recent progress in our understanding of Mycobacterium tuberculosis survival in macrophages, the interaction of M. tuberculosis with Toll-like receptors (TLRs) and the establishment of the link between innate and adaptive immunity, and TLRs and interferon-γ-mediated antimicrobial pathways in macrophages. We also propose a paradigm that TLR2 signaling regulates the magnitude of the host Th1 response leading to either M. tuberculosis persistence and latent infection or replication and disease.

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REFERENCES

  1. Metchnikoff E: Immunity to Infective Diseases. London, Cambridge University Press, 1905

    Google Scholar 

  2. World Health Organization: Anti-Tuberculosis Drug Resistance in the World: The WHO/IUTLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Geneva, Switzerland, World Health Organization, 2001

    Google Scholar 

  3. Murray JF: Tuberculosis and HIV infection: A global perspective. Respiration 65:335, 1998

    PubMed  CAS  Google Scholar 

  4. De Cock KM, Chaisson RE: Will DOTS do it? A reappraisal of tuberculosis control in countries with high rates of HIV infection. Int J Tuberc Lung Dis 3:457, 1999

    PubMed  CAS  Google Scholar 

  5. Pablos-Mendez A, Raviglione MC, Laszlo A, Binkin N, Rieder HL, Bustreo F, Cohn DL, Lambregts-van Weezenbeek CS, Kim SJ, Chaulet P, Nunn P: Global surveillance for antituberculosis-drug resistance, 1994–1997. World Health Organization–International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 338:1641, 1998

    PubMed  CAS  Google Scholar 

  6. Raviglione MC, Snider DE, Jr, Kochi A: Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 273:220, 1995

    PubMed  CAS  Google Scholar 

  7. Medzhitov R, Janeway CJ: The Toll receptor family and microbial recognition. Trends Microbiol 10:452, 2000

    Google Scholar 

  8. Kaisho T, Akira S: Critical roles of Toll-like receptors in host defense. Crit Rev Immunol 20:393, 2000

    PubMed  CAS  Google Scholar 

  9. Takeda K, Kaisho T, Akira S: Toll-like receptors. Annu Rev Immunol 21:335, 2003

    PubMed  CAS  Google Scholar 

  10. Aderem A, Ulevitch RJ: Toll-like receptors in the induction of the innate immune response. Nature 406:782, 2000

    PubMed  CAS  Google Scholar 

  11. Stead WW: Pathogenesis of a first episode of chronic pulmonary tuberculosis in man: Recrudescence of residuals of the primary infection or exogenous reinfection? Am Rev Respir Dis 95:729, 1967

    PubMed  CAS  Google Scholar 

  12. Stead WW: The pathogenesis of pulmonary tuberculosis among older persons. Am Rev Respir Dis 91:811, 1965

    PubMed  CAS  Google Scholar 

  13. Selwyn PA, Hartel D, Lewis VA, Schhoenbaum EE, Vermuns SH, Klein RS, Walker AT, Freidland GH: A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 320:545, 1989

    Article  PubMed  CAS  Google Scholar 

  14. Schlesinger LS, Bellinger-Kawahara CG, Payne NR, Horwitz MA: Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement C3. J Immunol 144:2771, 1990

    PubMed  CAS  Google Scholar 

  15. Ernst JD: Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 66:1277, 1998

    PubMed  CAS  Google Scholar 

  16. Beharka AA, Gaynor CD, Kang BK, Voelker DR, McCormack FX, Schlesinger LS: Pulmonary surfactant protein A up-regulates activity of the mannose receptor, a pattern recognition receptor expressed on human macrophages. J Immunol 169:3565, 2002

    PubMed  CAS  Google Scholar 

  17. Gaynor CD, McCormack FX, Voelker DR, McGowan SE, Schlesinger LS: Pulmonary surfactant protein A mediates enhanced phagocytosis of Mycobacterium tuberculosis by a direct interaction with human macrophages. J Immunol 155:5343, 1995

    PubMed  CAS  Google Scholar 

  18. Hu C, Mayadas TN, Tanaka K, Chan J, Salgame P: Mycobacterium tuberculosis infection in complement receptor 3-deficient mice. J Immunol 165:2596, 2000

    PubMed  CAS  Google Scholar 

  19. Gatfield J, Pieters J: Essential role for cholesterol in entry of mycobacteria into macrophages. Science 288:1647, 2000

    PubMed  CAS  Google Scholar 

  20. Armstrong JA, Hart PD: Response of cultured macrophages to M. tuberculosis with observations of fusion of lysosomes with phagosomes. J Exp Med 134:713, 1971

    PubMed  CAS  Google Scholar 

  21. Armstrong JA, Hart PD: Phagosome–lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival. J Exp Med 142:1, 1975

    PubMed  CAS  Google Scholar 

  22. 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 15:6960, 1996

    PubMed  CAS  Google Scholar 

  23. Clemens DL, Horwitz MA: The Mycobacterium tuberculosis phagosome interacts with early endosomes and is accessible to exogenously administered transferrin. J Exp Med 184:1349, 1996

    PubMed  CAS  Google Scholar 

  24. Russell DG, Dant J, Sturgill-Koszycki S: Mycobacterium avium- and Mycobacterium tuberculosis-containing vacuoles are dynamic, fusion-competent vesicles that are accessible to glycosphingolipids from the host cell plasmalemma. J Immunol 156:4764, 1996

    PubMed  CAS  Google Scholar 

  25. Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, Haddix PL, Collins HL, Fok AK, Allen RD, Gluck SL, Heuser J, Russell DG: Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 263:678, 1994

    PubMed  CAS  Google Scholar 

  26. Clemens DL, Lee BY, Horwitz MA: Deviant expression of Rab5 on phagosomes containing the intracellular pathogens Mycobacterium tuberculosis and Legionella pneumophila is associated with altered phagosomal fate. Infect Immun 68:2671, 2000

    PubMed  CAS  Google Scholar 

  27. Via LE, Deretic D, Ulmer RJ, Hibler NS, Huber LA, Deretic V: Arrest of mycobacterial phagosome maturation is caused by a block in vesicle fusion between stages controlled by Rab5 and Rab7. J Biol Chem 272:13326, 1997

    PubMed  CAS  Google Scholar 

  28. Fratti RA, Backer JM, Gruenberg J, Corvera S, Deretic V: Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J Cell Biol 154:631, 2001

    PubMed  CAS  Google Scholar 

  29. Deretic V, Vergne I, Chua J, Master S, Singh SB, Fazio JA, Kyei G: Endosomal membrane traffic: Convergence point targeted by Mycobacterium tuberculosis and HIV. Cell Microbiol 6:999, 2004

    PubMed  CAS  Google Scholar 

  30. Kusner DJ: Mechanisms of mycobacterial persistence in tuberculosis. Clin Immunol 114:239, 2005

    PubMed  CAS  Google Scholar 

  31. Anes E, Kuhnel MP, Bos E, Moniz-Pereira J, Habermann A, Griffiths G: Selected lipids activate phagosome actin assembly and maturation resulting in killing of pathogenic mycobacteria. Nat Cell Biol 5:793, 2003

    PubMed  CAS  Google Scholar 

  32. Kelley VA, Schorey JS: Mycobacterium’s arrest of phagosome maturation in macrophages requires Rab5 activity and accessibility to iron. Mol Biol Cell 14:3366, 2003

    PubMed  CAS  Google Scholar 

  33. Fratti RA, Chua J, Vergne I, Deretic V: Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc Natl Acad Sci USA 100:5437, 2003

    PubMed  CAS  Google Scholar 

  34. Chua J, Vergne I, Master S, Deretic V: A tale of two lipids: Mycobacterium tuberculosis phagosome maturation arrest. Curr Opin Microbiol 7:71, 2004

    PubMed  CAS  Google Scholar 

  35. Kang PB, Azad AK, Torrelles JB, Kaufman TM, Beharka A, Tibesar E, DesJardin LE, Schlesinger LS: The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J Exp Med 202:987, 2005

    PubMed  CAS  Google Scholar 

  36. Vergne I, Fratti RA, Hill PJ, Chua J, Belisle J, Deretic V: Mycobacterium tuberculosis phagosome maturation arrest: Mycobacterial phosphatidylinositol analog phosphatidylinositol mannoside stimulates early endosomal fusion. Mol Biol Cell 15:751, 2004

    PubMed  CAS  Google Scholar 

  37. Walburger A, Koul A, Ferrari G, Nguyen L, Prescianotto-Baschong C, Huygen K, Klebl B, Thompson C, Bacher G, Pieters J: Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304:1800, 2004

    PubMed  CAS  Google Scholar 

  38. Bodnar KA, Serbina NV, Flynn JL: Fate of Mycobacterium tuberculosis within murine dendritic cells. Infect Immun 69:800, 2001

    PubMed  CAS  Google Scholar 

  39. Tailleux L, Neyrolles O, Honore-Bouakline S, Perret E, Sanchez F, Abastado JP, Lagrange PH, Gluckman JC, Rosenzwajg M, Herrmann JL: Constrained intracellular survival of Mycobacterium tuberculosis in human dendritic cells. J Immunol 170:1939, 2003

    PubMed  CAS  Google Scholar 

  40. Pan H, Yan BS, Rojas M, Shebzukhov YV, Zhou H, Kobzik L, Higgins DE, Daly MJ, Bloom BR, Kramnik I: Ipr1 gene mediates innate immunity to tuberculosis. Nature 434:767, 2005

    PubMed  CAS  Google Scholar 

  41. Tosh K, Campbell SJ, Fielding K, Sillah J, Bah B, Gustafson P, Manneh K, Lisse I, Sirugo G, Bennett S, Aaby P, McAdam KP, Bah-Sow O, Lienhardt C, Kramnik I, Hill AV: Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa. Proc Natl Acad Sci USA 103:10364, 2006

    PubMed  CAS  Google Scholar 

  42. Thye T, Browne EN, Chinbuah MA, Gyapong J, Osei I, Owusu-Dabo E, Niemann S, Rusch-Gerdes S, Horstmann RD, Meyer CG: No associations of human pulmonary tuberculosis with Sp110 variants. J Med Genet 43:e32, 2006

    PubMed  CAS  Google Scholar 

  43. Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST, Brennan PJ, Bloom BR, Godowski PJ, Modlin RL: Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285:732, 1999

    PubMed  CAS  Google Scholar 

  44. Pecora ND, Gehring AJ, Canaday DH, Boom WH, Harding CV: Mycobacterium tuberculosis LprA is a lipoprotein agonist of TLR2 that regulates innate immunity and APC function. J Immunol 177:422, 2006

    PubMed  CAS  Google Scholar 

  45. Gehring AJ, Dobos KM, Belisle JT, Harding CV, Boom WH: Mycobacterium tuberculosis LprG (Rv1411c): A novel TLR-2 ligand that inhibits human macrophage class II MHC antigen processing. J Immunol 173:2660, 2004

    PubMed  CAS  Google Scholar 

  46. Quesniaux VJ, Nicolle DM, Torres D, Kremer L, Guerardel Y, Nigou J, Puzo G, Erard F, Ryffel B: Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independent-negative regulation of proinflammatory cytokines by mycobacterial lipomannans. J Immunol 172:4425, 2004

    PubMed  CAS  Google Scholar 

  47. Gilleron M, Himoudi N, Adam O, Constant P, Venisse A, Riviere M, Puzo G: Mycobacterium smegmatis phosphoinositols-glyceroarabinomannans. Structure and localization of alkali-labile and alkali-stable phosphoinositides. J Biol Chem 272:117, 1997

    PubMed  CAS  Google Scholar 

  48. Jones BW, Means TK, Heldwein KA, Keen MA, Hill PJ, Belisle JT, Fenton MJ: Different Toll-like receptor agonists induce distinct macrophage responses. J Leukoc Biol 69:1036, 2001

    PubMed  CAS  Google Scholar 

  49. Abel B, Thieblemont N, Quesniaux VJ, Brown N, Mpagi J, Miyake K, Bihl F, Ryffel B: Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice. J Immunol 169:3155, 2002

    PubMed  CAS  Google Scholar 

  50. Gilleron M, Nigou J, Nicolle D, Quesniaux V, Puzo G: The acylation state of mycobacterial lipomannans modulates innate immunity response through toll-like receptor 2. Chem Biol 13:39, 2006

    PubMed  CAS  Google Scholar 

  51. Means TK, Lien E, Yoshimura A, Wang S, Golenbock DT, Fenton MJ: The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors. J Immunol 163:6748, 1999

    PubMed  CAS  Google Scholar 

  52. Kamath AB, Alt J, Debbabi H, Behar SM: Toll-like receptor 4-defective C3H/HeJ mice are not more susceptible than other C3H substrains to infection with Mycobacterium tuberculosis. Infect Immun 71:4112, 2003

    PubMed  CAS  Google Scholar 

  53. Reiling N, Holscher C, Fehrenbach A, Kroger S, Kirschning CJ, Goyert S, Ehlers S: Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 169:3480, 2002

    PubMed  CAS  Google Scholar 

  54. Sugawara I, Yamada H, Li C, Mizuno S, Takeuchi O, Akira S: Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiol Immunol 47:327, 2003

    PubMed  CAS  Google Scholar 

  55. Noss EH, Pai RK, Sellati TJ, Radolf JD, Belisle J, Golenbock DT, Boom WH, Harding CV: Toll-like receptor 2-dependent inhibition of macrophage class II MHC expression and antigen processing by 19-kDa lipoprotein of Mycobacterium tuberculosis. J Immunol 167:910, 2001

    PubMed  CAS  Google Scholar 

  56. Fortune SM, Solache A, Jaeger A, Hill PJ, Belisle JT, Bloom BR, Rubin EJ, Ernst JD: Mycobacterium tuberculosis inhibits macrophage responses to IFN-gamma through myeloid differentiation factor 88-dependent and -independent mechanisms. J Immunol 172:6272, 2004

    PubMed  CAS  Google Scholar 

  57. Banaiee N, Kincaid EZ, Buchwald U, Jacobs WR, Jr, Ernst JD: Potent inhibition of macrophage responses to IFN-gamma by live virulent Mycobacterium tuberculosis is independent of mature mycobacterial lipoproteins but dependent on TLR2. J Immunol 176:3019, 2006

    PubMed  CAS  Google Scholar 

  58. Pompei L, Jang S, Zamlynny B, Ravikumar S, McBride A, Hickman SP, Salgame P: Disparity in interleukin-12 release in dendritic cells and macrophages in response to Mycobacterium tuberculosis is due to utilization of distinct Toll-like receptors. J Immunol, 2007 (in press)

  59. Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A: TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 202:1715, 2005

    PubMed  CAS  Google Scholar 

  60. Flynn JL, Chan J: Immunology of tuberculosis. Annu Rev Immunol 19:93, 2001

    PubMed  CAS  Google Scholar 

  61. Denis M: Killing of Mycobacterium tuberculosis within human monocytes: Activation by cytokines and calcitriol. Clin Exp Immunol 84:200, 1991

    Article  PubMed  CAS  Google Scholar 

  62. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M, Davidson RN: Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: A case–control study. Lancet 355:618, 2000

    PubMed  CAS  Google Scholar 

  63. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770, 2006

    PubMed  CAS  Google Scholar 

  64. Auricchio G, Garg SK, Martino A, Volpe E, Ciaramella A, De Vito P, Baldini PM, Colizzi V, Fraziano M: Role of macrophage phospholipase D in natural and CpG-induced antimycobacterial activity. Cell Microbiol 5:913, 2003

    PubMed  CAS  Google Scholar 

  65. Russell DG: Who puts the tubercle in tuberculosis? Nat Rev Microbiol 5:39, 2007

    PubMed  CAS  Google Scholar 

  66. Ulrichs T, Kaufmann SH: New insights into the function of granulomas in human tuberculosis. J Pathol 208:261, 2006

    PubMed  CAS  Google Scholar 

  67. Salgame P: Host innate and Th1 responses and the bacterial factors that control Mycobacterium tuberculosis infection. Curr Opin Immunol 17:374, 2005

    PubMed  CAS  Google Scholar 

  68. Estaquier J, Idziorek T, Weiping Z, Emilie D, Farber C-M, Bourez J-M, Ameisen JC: T helper type 1/T helper type 2 cytokines and T cell death: Preventive effect of IL-12 on activation-induced and CD95 (Fas/Apo-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J Exp Med 182:1759, 1995

    PubMed  CAS  Google Scholar 

  69. Rosenzweig SD, Holland SM: Defects in the interferon-gamma and interleukin-12 pathways. Immunol Rev 203:38, 2005

    PubMed  CAS  Google Scholar 

  70. Brombacher F, Kastelein RA, Alber G: Novel IL-12 family members shed light on the orchestration of Th1 responses. Trends Immunol 24:207, 2003

    PubMed  CAS  Google Scholar 

  71. Zhang M, Gong J, Iyer DV, Jones BE, Modlin RL, Barnes PF: T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest 94:2435, 1994

    PubMed  CAS  Google Scholar 

  72. Giacomini E, Iona E, Ferroni L, Miettinen M, Fattorini L, Orefici G, Julkunen I, Coccia EM: Infection of human macrophages and dendritic cells with Mycobacterium tuberculosis induces a differential cytokine gene expression that mosulates T cell response. J Immunol 166:7033, 2001

    PubMed  CAS  Google Scholar 

  73. Hickman SP, Chan J, Salgame P: Mycobacterium tuberculosis induces differential cytokine production from dendritic cells and macrophages with divergent effects on naive T cell polarization. J Immunol 168:4636, 2002

    PubMed  CAS  Google Scholar 

  74. Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A, de Waal-Malefyt R, Ottenhoff TH: Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci USA 101:4560, 2004

    PubMed  CAS  Google Scholar 

  75. Flynn J, Goldstein M, Triebold K, Sypek J, Wolf S, Bloom B: IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection. J Immunol 155:2515, 1995

    PubMed  CAS  Google Scholar 

  76. Castro A, Silva R, Appelberg R: Endogenously produced IL-12 is required for the induction of protective T cells during Mycobacterium avium infections in mice. J Immunol 155:2013, 1995

    PubMed  CAS  Google Scholar 

  77. Feng CG, Jankovic D, Kullberg M, Cheever A, Scanga CA, Hieny S, Caspar P, Yap GS, Sher A: Maintenance of pulmonary Th1 effector function in chronic tuberculosis requires persistent IL-12 production. J Immunol 174:4185, 2005

    PubMed  CAS  Google Scholar 

  78. Khader SA, Pearl JE, Sakamoto K, Gilmartin L, Bell GK, Jelley-Gibbs DM, Ghilardi N, deSauvage F, Cooper AM: IL-23 Compensates for the Absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-{gamma} responses if IL-12p70 is available. J Immunol 175:788, 2005

    PubMed  CAS  Google Scholar 

  79. Chackerian AA, Chen S-J, Brodie SJ, Mattson JD, McClanahan TK, Kastelein RA, Bowman EP: Neutralization or absence of the interleukin-23 pathway does not compromise immunity to mycobacterial infection. Infect Immun 74:6092, 2006

    PubMed  CAS  Google Scholar 

  80. Cooper AM, Kipnis A, Turner J, Magram J, Ferrante J, Orme IM: Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J Immunol 168:1322, 2002

    PubMed  CAS  Google Scholar 

  81. Happel KI, Lockhart EA, Mason CM, Porretta E, Keoshkerian E, Odden AR, Nelson S, Ramsay AJ: Pulmonary interleukin-23 gene delivery increases local T-cell immunity and controls growth of Mycobacterium tuberculosis in the lungs. Infect Immun 73:5782, 2005

    PubMed  CAS  Google Scholar 

  82. Hunter CA: New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 5:521, 2005

    PubMed  CAS  Google Scholar 

  83. Pearl JE, Khader SA, Solache A, Gilmartin L, Ghilardi N, deSauvage F, Cooper AM: IL-27 signaling compromises control of bacterial growth in mycobacteria-infected mice. J Immunol 173:7490, 2004

    PubMed  CAS  Google Scholar 

  84. Artis D, Johnson LM, Joyce K, Saris C, Villarino A, Hunter CA, Scott P: Cutting edge: Early IL-4 production governs the requirement for IL-27-WSX-1 signaling in the development of protective Th1 cytokine responses following Leishmania major infection. J Immunol 172:4672, 2004

    PubMed  CAS  Google Scholar 

  85. Villarino A, Hibbert L, Lieberman L, Wilson E, Mak T, Yoshida H, Kastelein RA, Saris C, Hunter CA: The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19:645, 2003

    PubMed  CAS  Google Scholar 

  86. Villarino AV, Huang E, Hunter CA: Understanding the pro- and anti-inflammatory properties of IL-27. J Immunol 173:715, 2004

    PubMed  CAS  Google Scholar 

  87. Stenger S: Immunological control of tuberculosis: Role of tumour necrosis factor and more. Ann Rheum Dis 64(Suppl 4):iv24, 2005

    PubMed  CAS  Google Scholar 

  88. Chan J, Xing Y, Magliozzo R, Bloom B: Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. J Exp Med 175:1111, 1992

    PubMed  CAS  Google Scholar 

  89. Keane J, Balcewicz-Sablinska MR, Remold HG, Chupp GL, Meek BB, Fenton MJ, Kornfeld H: Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect Immun 65:298, 1997

    PubMed  CAS  Google Scholar 

  90. Winau F, Weber S, Sad S, de Diego J, Hoops SL, Breiden B, Sandhoff K, Brinkmann V, Kaufmann SHE, Schaible UE: Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity 24:105, 2006

    PubMed  CAS  Google Scholar 

  91. Balcewicz-Sablinska MK, Keane J, Kornfeld H, Remold HG: Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha. J Immunol 161:2636, 1998

    PubMed  CAS  Google Scholar 

  92. Engele M, Castiglione K, Schwerdtner N, Wagner M, Bolcskei P, Rollinghoff M, Stenger S: Induction of TNF in human alveolar macrophages as a potential evasion mechanism of virulent Mycobacterium tuberculosis. J Immunol 168:1328, 2002

    PubMed  CAS  Google Scholar 

  93. Kindler V, Sappino A-P, Grau GE, Piguet P-F, Vassalli P: The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 56:731, 1989

    PubMed  CAS  Google Scholar 

  94. Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Loenstein CL, Schreiber R, Mak TW, Bloom BR: Tumor necrosis factor is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2:561, 1995

    PubMed  CAS  Google Scholar 

  95. Roach DR, Bean AGD, Demangel C, France MP, Briscoe H, Britton WJ: TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 168:4620, 2002

    PubMed  CAS  Google Scholar 

  96. Algood HMS, Chan J, Flynn JL: Chemokines and tuberculosis. Cytokine Growth Factor Rev 14:467, 2003

    PubMed  CAS  Google Scholar 

  97. Algood HMS, Lin PL, Flynn JL: Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis 41:S189, 2005

    PubMed  CAS  Google Scholar 

  98. Tufariello JM, Chan J, Flynn JL: Latent tuberculosis: Mechanisms of host and bacillus that contribute to persistent infection. Lancet Infect Dis 3:578, 2003

    PubMed  CAS  Google Scholar 

  99. Mohan VP, Scanga CA, Yu K, Scott HM, Tanaka KE, Tsang E, Tsai MM, Flynn JL, Chan J: Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: Possible role for limiting pathology. Infect Immun 69:1847, 2001

    PubMed  CAS  Google Scholar 

  100. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM: Tuberculosis associated with infliximab, a tumor necrosis factor {alpha}-neutralizing agent. N Engl J Med 345:1098, 2001

    PubMed  CAS  Google Scholar 

  101. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, Vinh DC: Anti-tumour necrosis factor agents and tuberculosis risk: Mechanisms of action and clinical management. Lancet Infect Dis 3:148, 2003

    PubMed  CAS  Google Scholar 

  102. Peters W, Ernst JD: Mechanisms of cell recruitment in the immune response to Mycobacterium tuberculosis. Microbes Infect 5:151, 2003

    PubMed  CAS  Google Scholar 

  103. Orlova MO, Majorov KB, Lyadova IV, Eruslanov EB, M’lan CE, Greenwood CMT, Schurr E, Apt AS: Constitutive differences in gene expression profiles parallel genetic patterns of susceptibility to tuberculosis in mice. Infect Immun 74:3668, 2006

    PubMed  CAS  Google Scholar 

  104. Tessier P, Naccache P, Clark-Lewis I, Gladue R, Neote K, McColl S: Chemokine networks in vivo: Involvement of C-X-C and C-C chemokines in neutrophil extravasation in vivo in response to TNF-alpha. J Immunol 159:3595, 1997

    PubMed  CAS  Google Scholar 

  105. Lande R, Giacomini E, Grassi T, Remoli ME, Iona E, Miettinen M, Julkunen I, Coccia EM: IFN-alpha beta released by Mycobacterium tuberculosis-infected human dendritic cells induces the expression of CXCL10: Selective recruitment of NK and activated T cells. J Immunol 170:1174, 2003

    PubMed  CAS  Google Scholar 

  106. Peters W, Scott HM, Chambers HF, Flynn JL, Charo IF, Ernst JD: Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc Natl Acad Sci USA 98:7958, 2001

    PubMed  CAS  Google Scholar 

  107. Scott HM, Flynn JL: Mycobacterium tuberculosis in chemokine receptor 2-deficient mice: Influence of dose on disease progression. Infect Immun 70:5946, 2002

    PubMed  CAS  Google Scholar 

  108. Peters W, Cyster JG, Mack M, Schlondorff D, Wolf AJ, Ernst JD, Charo IF: CCR2-dependent trafficking of F4/80dim macrophages and CD11cdim/intermediate dendritic cells is crucial for T cell recruitment to lungs infected with Mycobacterium tuberculosis. J Immunol 172:7647, 2004

    PubMed  CAS  Google Scholar 

  109. Kipnis A, Basaraba RJ, Orme IM, Cooper AM: Role of chemokine ligand 2 in the protective response to early murine pulmonary tuberculosis. Immunology 109:547, 2003

    PubMed  CAS  Google Scholar 

  110. Floto RA, MacAry PA, Boname JM, Mien TS, Kampmann B, Hair JR, Huey OS, Houben ENG, Pieters J, Day C, Oehlmann W, Singh M, Smith KGC, Lehner PJ: Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5. Science 314:454, 2006

    PubMed  CAS  Google Scholar 

  111. Badewa AP, Quinton LJ, Shellito JE, Mason CM: Chemokine receptor 5 and its ligands in the immune response to murine tuberculosis. Tuberculosis 85:185, 2005

    PubMed  CAS  Google Scholar 

  112. Algood HM, Flynn JL: CCR5-deficient mice control Mycobacterium tuberculosis infection despite increased pulmonary lymphocytic infiltration. J Immunol 173:3287, 2004

    PubMed  Google Scholar 

  113. Kahnert A, Hopken UE, Stein M, Bandermann S, Lipp M, Kaufmann SHE: Mycobacterium tuberculosis triggers formation of lymphoid structure in murine lungs. J Infect Dis 195:46, 2007

    PubMed  CAS  Google Scholar 

  114. Seiler P, Aichele P, Bandermann S, Hauser AE, Lu B, Gerard NP, Gerard C, Ehlers S, Mollenkopf HJ, Kaufmann SH: Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3-signaling chemokines. Eur J Immunol 33:2676, 2003

    PubMed  CAS  Google Scholar 

  115. Chakravarty SD, Xu J, Lu B, Gerard C, Flynn J, Chan J: The chemokine receptor CXCR3 attenuates the control of chronic Mycobacterium tuberculosis infection in BALB/c mice. J Immunol 178:1723, 2007

    PubMed  CAS  Google Scholar 

  116. Bromley SK, Peterson DA, Gunn MD, Dustin ML: Cutting edge: Hierarchy of chemokine receptor and TCR signals regulating T cell migration and proliferation. J Immunol 165:15, 2000

    PubMed  CAS  Google Scholar 

  117. Jang S, Uematsu S, Akira S, Salgame P: IL-6 and IL-10 induction from dendritic cells in response to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition. J Immunol 173:3392, 2004

    PubMed  CAS  Google Scholar 

  118. Boussiotis VA, Tsai EY, Yunis EJ, Thim S, Delgado JC, Dascher CC, Berezovskaya A, Rousset D, Reynes JM, Goldfeld AE: IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest 105:1317, 2000

    Article  PubMed  CAS  Google Scholar 

  119. Gerosa F, Nisii C, Righetti S, Micciolo R, Marchesini M, Cazzadori A, Trinchieri G: CD4+ T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol 92:224, 1999

    PubMed  CAS  Google Scholar 

  120. Hirsch CS, Toossi Z, Othieno C, Johnson JL, Schwander SK, Robertson S, Wallis RS, Edmonds K, Okwera A, Mugerwa R, Peters P, Ellner JJ: Depressed T-cell interferon-gamma responses in pulmonary tuberculosis: Analysis of underlying mechanisms and modulation with therapy. J Infect Dis 180:2069, 1999

    PubMed  CAS  Google Scholar 

  121. Barnes PF, Lu S, Abrams JS, Wang E, Yamamura M, Modlin RL: Cytokine production at the site of disease in human tuberculosis. Infect Immun 61:3482, 1993

    PubMed  CAS  Google Scholar 

  122. Fulton SA, Cross JV, Toossi ZT, Boom WH: Regulation of interleukin-12 by interleukin-10, transforming growth factor-beta, tumor necrosis factor-alpha, and interferon-gamma in human monocytes infected with Mycobacterium tuberculosis H37Ra. J Infect Dis 178:1105, 1998

    PubMed  CAS  Google Scholar 

  123. De La Barrera S, Aleman M, Musella R, Schierloh P, Pasquenelli V, Garcia V, Abbate E, Sasiain M, Del C: IL-10 down-regulates costimulatory molecules on Mycobacterium tuberculosis-pulsed macrophages and impairs the lytic activity of CD4 and CD8 CTL in tuberculosis patients. Clin Exp Immunol 138:128, 2004

    PubMed  CAS  Google Scholar 

  124. Rojas RE, Balaji KN, Subramanian A, Boom WH: Regulation of human CD4+ alpha beta T-cell-receptor-positive (TCR+) and gamma delta TCR+ T-cell responses to Mycobacterium tuberculosis by interleukin-10 and transforming growth factor beta. Infect Immun 67:6461, 1999

    PubMed  CAS  Google Scholar 

  125. North RJ: Mice incapable of making IL-4 or IL-10 display normal resistance to infection with Mycobacterium tuberculosis. Clin Exp Immunol 113:55, 1998

    PubMed  CAS  Google Scholar 

  126. Turner J, Gonzalez-Juarrero M, Ellis DL, Basaraba RJ, Kipnis A, Orme IM, Cooper AM: in vivo IL-10 production reactivates chronic pulmonary tuberculosis in C57BL/6 mice. J Immunol 169:6343, 2002

    PubMed  CAS  Google Scholar 

  127. Feng CG, Kullberg MC, Jankovic D, Cheever AW, Caspar P, Coffman RL, Sher A: Transgenic mice expressing human interleukin-10 in the antigen-presenting cell compartment show increased susceptibility to infection with Mycobacterium avium associated with decreased macrophage effector function and apoptosis. Infect Immun 70:6672, 2002

    PubMed  CAS  Google Scholar 

  128. Awomoyi AA, Marchant A, Howson JM, McAdam KP, Blackwell JM, Newport MJ: Interleukin-10, polymorphism in SLC11A1 (formerly NRAMP1), and susceptibility to tuberculosis. J Infect Dis 186:1808, 2002

    PubMed  CAS  Google Scholar 

  129. Buettner M, Meinken C, Bastian M, Bhat R, Stossel E, Faller G, Cianciolo G, Ficker J, Wagner M, Rollinghoff M, Stenger S: Inverse correlation of maturity and antibacterial activity in human dendritic cells. J Immunol 174:4203, 2005

    PubMed  CAS  Google Scholar 

  130. Bhatt K, Hickman SP, Salgame P: Cutting edge: A new approach to modeling early lung immunity in murine tuberculosis. J Immunol 172:2748, 2004

    PubMed  CAS  Google Scholar 

  131. Humphreys IR, Stewart GR, Turner DJ, Patel J, Karamanou D, Snelgrove RJ, Young DB: A role for dendritic cells in the dissemination of mycobacterial infection. Microbes Infect 8:1339, 2006

    PubMed  CAS  Google Scholar 

  132. Jiao X, Lo-Man R, Guermonprez P, Fiette L, Deriaud E, Burgaud S, Gicquel B, Winter N, Leclerc C: Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity. J Immunol 168:1294, 2002

    PubMed  CAS  Google Scholar 

  133. Tian T, Woodworth J, Skold M, Behar SM: in vivo depletion of CD11c+ cells delays the CD4+ T cell response to Mycobacterium tuberculosis and exacerbates the outcome of infection. J Immunol 175:3268, 2005

    PubMed  CAS  Google Scholar 

  134. Abadie V, Badell E, Douillard P, Ensergueix D, Leenen PJ, Tanguy M, Fiette L, Saeland S, Gicquel B, Winter N: Neutrophils rapidly migrate via lymphatics after Mycobacterium bovis BCG intradermal vaccination and shuttle live bacilli to the draining lymph nodes. Blood 106:1843, 2005

    PubMed  CAS  Google Scholar 

  135. Pedrosa J, Saunders BM, Appelberg R, Orme IM, Silva MT, Cooper AM: Neutrophils play a protective nonphagocytic role in systemic Mycobacterium tuberculosis infection of mice. Infect Immun 68:577, 2000

    PubMed  CAS  Google Scholar 

  136. Tsai MC, Chakravarty S, Zhu G, Xu J, Tanaka K, Koch C, Tufariello J, Flynn J, Chan J: Characterization of the tuberculous granuloma in murine and human lungs: Cellular composition and relative tissue oxygen tension. Cell Microbiol 8:218, 2006

    PubMed  CAS  Google Scholar 

  137. Schaible UE, Winau F, Sieling PA, Fischer K, Collins HL, Hagens K, Modlin RL, Brinkmann V, Kaufmann SH: Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat Med 9:1039, 2003

    PubMed  CAS  Google Scholar 

  138. Makino M, Maeda Y, Mukai T, Kaufmann SH: Impaired maturation and function of dendritic cells by mycobacteria through IL-1beta. Eur J Immunol 36:1443, 2006

    PubMed  CAS  Google Scholar 

  139. Hanekom WA, Mendillo M, Manca C, Haslett PA, Siddiqui MR, Barry C, III, Kaplan G: Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro. J Infect Dis 188:257, 2003

    PubMed  CAS  Google Scholar 

  140. Khader SA, Partida-Sanchez S, Bell G, Jelley-Gibbs DM, Swain S, Pearl JE, Ghilardi N, deSauvage FJ, Lund FE, Cooper AM: Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J Exp Med 203:1805, 2006

    PubMed  CAS  Google Scholar 

  141. Demangel C, Bertolino P, Britton WJ: Autocrine IL-10 impairs dendritic cell (DC)-derived immune responses to mycobacterial infection by suppressing DC trafficking to draining lymph nodes and local IL-12 production. Eur J Immunol 32:994, 2002

    PubMed  CAS  Google Scholar 

  142. Flynn JL, Chan J: Immune evasion by Mycobacterium tuberculosis: Living with the enemy. Curr Opin Immunol 15:450, 2003

    PubMed  CAS  Google Scholar 

  143. Dayaram YK, Talaue MT, Connell ND, Venketaraman V: Characterization of a glutathione metabolic mutant of Mycobacterium tuberculosis and its resistance to glutathione and nitrosoglutathione. J Bacteriol 188:1364, 2006

    PubMed  CAS  Google Scholar 

  144. Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski PJ, Bloom BR, Modlin RL: Induction of direct antimicrobial activity through mammalian Toll-like receptors. Science 291:1544, 2001

    PubMed  CAS  Google Scholar 

  145. Nozaki Y, Hasegawa Y, Ichiyama S, Nakashima I, Shimokata K: Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages. Infect Immun 65:3644, 1997

    PubMed  CAS  Google Scholar 

  146. MacMicking JD, Taylor GA, McKinney JD: Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science 302:654, 2003

    PubMed  CAS  Google Scholar 

  147. Deretic V: Autophagy as an immune defense mechanism. Curr Opin Immunol 18:375, 2006

    PubMed  CAS  Google Scholar 

  148. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V: Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753, 2004

    PubMed  CAS  Google Scholar 

  149. Ferrero E, Biswas P, Vettoretto K, Ferrarini M, Uguccioni M, Piali L, Leone BE, Moser B, Rugarli C, Pardi R: Macrophages exposed to Mycobacterium tuberculosis release chemokines able to recruit selected leucocyte subpopulations: Focus on γδ cells. Immunology 108:365, 2003

    PubMed  CAS  Google Scholar 

  150. Lockhart E, Green AM, Flynn JL: IL-17 production is dominated by {gamma}{delta} T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol 177:4662, 2006

    PubMed  CAS  Google Scholar 

  151. Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ: The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J Exp Med 193:271, 2001

    PubMed  CAS  Google Scholar 

  152. Saunders BM, Frank AA, Cooper AM, Orme IM: Role of gamma delta T cells in immunopathology of pulmonary Mycobacterium avium infection in mice. Infect Immun 66:5508, 1998

    PubMed  CAS  Google Scholar 

  153. Munk M, Gatrill A, Kaufmann S: Target cell lysis and IL-2 secretion by gamma/delta T lymphocytes after activation with bacteria. J Immunol 145:2434, 1990

    PubMed  CAS  Google Scholar 

  154. Chen ZW: Immune regulation of [gamma][delta] T cell responses in mycobacterial infections. Clin Immunol 116:202, 2005

    PubMed  CAS  Google Scholar 

  155. Shen Y, Zhou D, Qiu L, Lai X, Simon M, Shen L, Kou Z, Wang Q, Jiang L, Estep J, Hunt R, Clagett M, Sehgal PK, Li Y, Zeng X, Morita CT, Brenner MB, Letvin NL, Chen ZW: Adaptive immune response of Vgamma 2Vdelta 2+ T cells during mycobacterial infections. Science 295:2255, 2002

    PubMed  CAS  Google Scholar 

  156. Li B, Rossman M, Imir T, Oner-Eyuboglu A, Lee C, Biancaniello R, Carding S: Disease-specific changes in gamma delta T cell repertoire and function in patients with pulmonary tuberculosis. J Immunol 157:4222, 1996

    PubMed  CAS  Google Scholar 

  157. Vankayalapati R, Garg A, Porgador A, Griffith DE, Klucar P, Safi H, Girard WM, Cosman D, Spies T, Barnes PF: Role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with an intracellular bacterium. J Immunol 175:4611, 2005

    PubMed  CAS  Google Scholar 

  158. Junqueira-Kipnis AP, Kipnis A, Jamieson A, Juarrero MG, Diefenbach A, Raulet DH, Turner J, Orme IM: NK cells respond to pulmonary infection with Mycobacterium tuberculosis, but play a minimal role in protection. J Immunol 171:6039, 2003

    PubMed  CAS  Google Scholar 

  159. Feng CG, Kaviratne M, Rothfuchs AG, Cheever A, Hieny S, Young HA, Wynn TA, Sher A: NK cell-derived IFN-{gamma} differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis. J Immunol 177:7086, 2006

    PubMed  CAS  Google Scholar 

  160. Gansert JL, Kiebler V, Engele M, Wittke F, Rollinghoff M, Krensky AM, Porcelli SA, Modlin RL, Stenger S: Human NKT cells express granulysin and exhibit antimycobacterial activity. J Immunol 170:3154, 2003

    PubMed  CAS  Google Scholar 

  161. Apostolou I, Takahama Y, Belmant C, Kawano T, Huerre M, Marchal G, Cui J, Taniguchi M, Nakauchi H, Fournie J-J, Kourilsky P, Gachelin G: Murine natural killer cells contribute to the granulomatous reaction caused by mycobacterial cell walls. PNAS 96:5141, 1999

    PubMed  CAS  Google Scholar 

  162. Chackerian A, Alt J, Perera V, Behar SM: Activation of NKT cells protects mice from tuberculosis. Infect Immun 70:6302, 2002

    PubMed  CAS  Google Scholar 

  163. Aliberti J, Bafica A: Anti-inflammatory pathways as a host evasion mechanism for pathogens. Prostaglandins Leukot Essent Fatty Acids 73:283, 2005

    PubMed  CAS  Google Scholar 

  164. Reed MB, Domenech P, Manca C, Su H, Barczak AK, Kreiswirth BN, Kaplan G, Barry CE, III: A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431:84, 2004

    PubMed  CAS  Google Scholar 

  165. Ribeiro-Rodrigues R, Resende Co T, Rojas R, Toossi Z, Dietze R, Boom WH, Maciel E, Hirsch CS: A role for CD4+CD25+ T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol 144:25, 2006

    PubMed  CAS  Google Scholar 

  166. Guyot-Revol V, Innes JA, Hackforth S, Hinks T, Lalvani A: Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. Am J Respir Crit Care Med 173:803, 2006

    PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS

This work was supported in part by the NIH grants AI-49778 and AI-55377 to PS.

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  1. Department of Medicine, Centre for Emerging Pathogens, UMDNJ-New Jersey Medical School, MSB A902, 185 South Orange Avenue, Newark, New Jersey, 07101, USA

    Kamlesh Bhatt & Padmini Salgame

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  1. Kamlesh Bhatt
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  2. Padmini Salgame
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Correspondence to Padmini Salgame.

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Bhatt, K., Salgame, P. Host Innate Immune Response to Mycobacterium tuberculosis . J Clin Immunol 27, 347–362 (2007). https://doi.org/10.1007/s10875-007-9084-0

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