Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Immunology of tuberculosis

Lee W Riley, MD
Section Editor
C Fordham von Reyn, MD
Deputy Editor
Elinor L Baron, MD, DTMH


The human host serves as the only natural reservoir for Mycobacterium tuberculosis. The ability of the organism to efficiently establish latent infection has enabled it to spread to nearly one-third of the world's population [1]. According to the 2014 World Health Organization report, an estimated 9 million people developed tuberculosis and 1.5 million died [2]. The progression from latent tuberculosis infection to active disease remains poorly understood. Given the magnitude of the health problem and the emergence of drug-resistant strains of the organism, a better understanding of the immunology of this disease and the development of an effective vaccine are highly desirable. (See "Epidemiology of tuberculosis".)

The immunology of M. tuberculosis will be reviewed here. The microbiology and pathogenesis of this infection, including virulence factors, tropism for the lungs, and latency factors, are discussed separately. (See "Natural history, microbiology, and pathogenesis of tuberculosis".)


The majority of individuals in the general population who become infected with M. tuberculosis never develop clinical disease [3]. This demonstrates that the innate and adaptive immune response of the host in controlling tuberculosis (TB) infection is effective. Mycobacterial and host factors that adversely affect these two arms of the immune system contribute to latent tuberculosis infection (LTBI) and active disease.

Host factors

Innate immunity — The pathophysiology of innate immune response during first encounter of M. tuberculosis with lung cells remains poorly characterized. In the average human alveolus, there are more than 28,000 epithelial cells (pneumocytes) and about 50 macrophages [4,5]. Mouse studies have shown that after about 14 days of infection, the predominant cell type infected with M. tuberculosis is the myeloid dendritic cell rather than the alveolar macrophage [6]. Thus, during the very early phase of lung infection, the interaction of M. tuberculosis with lung epithelial cells may affect later dendritic cell and alveolar macrophage migration and ultimately clinical outcome. Little is known about what happens during this early phase.

Once M. tuberculosis comes into contact with dendritic or alveolar macrophages, the interaction of these cells with M. tuberculosis first involves recognition by these cells of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) located on the cell surface or in the cytosol [7]. Distinct sets of macrophage PRRs recognize distinct sets of MAMPs of M. tuberculosis. These PRRs serve to trigger innate immune response against molecules recognized to be foreign to the host cell. The recognition of M. tuberculosis by a group of PRRs called toll-like receptors (TLRs) triggers cell signal transduction that induces a proinflammatory response that is supposed to control the infection [8]. However, M. tuberculosis has evolved to subvert these host responses for its own survival in the host.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Sep 30, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Kunnath-Velayudhan S, Gennaro ML. Immunodiagnosis of tuberculosis: a dynamic view of biomarker discovery. Clin Microbiol Rev 2011; 24:792.
  2. World Health Organization. Global Tuberculosis Report 2014. http://www.who.int/tb/publications/global_report/en/ (Accessed on July 07, 2015).
  3. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis 1982; 125:8.
  4. Schneeberger EE. Alveolar type II cells. In: The lung: Scientific foundations, Crystal RJ, West JB (Eds), Raven Press, New York 1991. p.736.
  5. Crystal RJ. Alveolar macrophages. In: The lung: Scientific foundations, Crystal RJ, West JB (Eds), Raven Press, New York 1991. p.527.
  6. Wolf AJ, Linas B, Trevejo-Nuñez GJ, et al. Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J Immunol 2007; 179:2509.
  7. Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria. Immunol Rev 2015; 264:182.
  8. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11:373.
  9. Belvin MP, Anderson KV. A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol 1996; 12:393.
  10. Means TK, Wang S, Lien E, et al. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 1999; 163:3920.
  11. Yang RB, Mark MR, Gray A, et al. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 1998; 395:284.
  12. Schwandner R, Dziarski R, Wesche H, et al. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 1999; 274:17406.
  13. Underhill DM, Ozinsky A, Smith KD, Aderem A. Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc Natl Acad Sci U S A 1999; 96:14459.
  14. Thoma-Uszynski S, Stenger S, Takeuchi O, et al. Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 2001; 291:1544.
  15. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311:1770.
  16. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003; 21:335.
  17. Shi S, Nathan C, Schnappinger D, et al. MyD88 primes macrophages for full-scale activation by interferon-gamma yet mediates few responses to Mycobacterium tuberculosis. J Exp Med 2003; 198:987.
  18. Fremond CM, Yeremeev V, Nicolle DM, et al. Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J Clin Invest 2004; 114:1790.
  19. Najmi N, Kaur G, Sharma SK, Mehra NK. Human Toll-like receptor 4 polymorphisms TLR4 Asp299Gly and Thr399Ile influence susceptibility and severity of pulmonary tuberculosis in the Asian Indian population. Tissue Antigens 2010; 76:102.
  20. Newport MJ, Allen A, Awomoyi AA, et al. The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia. Tuberculosis (Edinb) 2004; 84:347.
  21. Carmona J, Cruz A, Moreira-Teixeira L, et al. Mycobacterium tuberculosis Strains Are Differentially Recognized by TLRs with an Impact on the Immune Response. PLoS One 2013; 8:e67277.
  22. Chan J, Fan XD, Hunter SW, et al. Lipoarabinomannan, a possible virulence factor involved in persistence of Mycobacterium tuberculosis within macrophages. Infect Immun 1991; 59:1755.
  23. Schlesinger LS, Bellinger-Kawahara CG, Payne NR, Horwitz MA. Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J Immunol 1990; 144:2771.
  24. Schlesinger LS. Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J Immunol 1993; 150:2920.
  25. Yuan Y, Lee RE, Besra GS, et al. Identification of a gene involved in the biosynthesis of cyclopropanated mycolic acids in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 1995; 92:6630.
  26. Sequeira PC, Senaratne RH, Riley LW. Inhibition of toll-like receptor 2 (TLR-2)-mediated response in human alveolar epithelial cells by mycolic acids and Mycobacterium tuberculosis mce1 operon mutant. Pathog Dis 2014; 70:132.
  27. Deretic V, Philipp W, Dhandayuthapani S, et al. Mycobacterium tuberculosis is a natural mutant with an inactivated oxidative-stress regulatory gene: implications for sensitivity to isoniazid. Mol Microbiol 1995; 17:889.
  28. Sherman DR, Sabo PJ, Hickey MJ, et al. Disparate responses to oxidative stress in saprophytic and pathogenic mycobacteria. Proc Natl Acad Sci U S A 1995; 92:6625.
  29. Philips JA. Mycobacterial manipulation of vacuolar sorting. Cell Microbiol 2008; 10:2408.
  30. Bach H, Papavinasasundaram KG, Wong D, et al. Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. Cell Host Microbe 2008; 3:316.
  31. Sun J, Wang X, Lau A, et al. Mycobacterial nucleoside diphosphate kinase blocks phagosome maturation in murine RAW 264.7 macrophages. PLoS One 2010; 5:e8769.
  32. Armstrong JA, Hart PD. Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J Exp Med 1971; 134:713.
  33. 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 1975; 142:1.
  34. McDonough KA, Kress Y, Bloom BR. Pathogenesis of tuberculosis: interaction of Mycobacterium tuberculosis with macrophages. Infect Immun 1993; 61:2763.
  35. Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, et al. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 1994; 263:678.
  36. Xu S, Cooper A, Sturgill-Koszycki S, et al. Intracellular trafficking in Mycobacterium tuberculosis and Mycobacterium avium-infected macrophages. J Immunol 1994; 153:2568.
  37. 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.
  38. Pancholi P, Mirza A, Schauf V, et al. Presentation of mycobacterial antigens by human dendritic cells: lack of transfer from infected macrophages. Infect Immun 1993; 61:5326.
  39. Wadee AA, Kuschke RH, Dooms TG. The inhibitory effects of Mycobacterium tuberculosis on MHC class II expression by monocytes activated with riminophenazines and phagocyte stimulants. Clin Exp Immunol 1995; 100:434.
  40. Noss EH, Pai RK, Sellati TJ, et al. Toll-like receptor 2-dependent inhibition of macrophage class II MHC expression and antigen processing by 19-kDa lipoprotein of Mycobacterium tuberculosis. J Immunol 2001; 167:910.
  41. van der Wel N, Hava D, Houben D, et al. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 2007; 129:1287.
  42. de Jonge MI, Pehau-Arnaudet G, Fretz MM, et al. ESAT-6 from Mycobacterium tuberculosis dissociates from its putative chaperone CFP-10 under acidic conditions and exhibits membrane-lysing activity. J Bacteriol 2007; 189:6028.
  43. Smith J, Manoranjan J, Pan M, et al. Evidence for pore formation in host cell membranes by ESX-1-secreted ESAT-6 and its role in Mycobacterium marinum escape from the vacuole. Infect Immun 2008; 76:5478.
  44. Pandey AK, Yang Y, Jiang Z, et al. NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis. PLoS Pathog 2009; 5:e1000500.
  45. Stanley SA, Johndrow JE, Manzanillo P, Cox JS. The Type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis. J Immunol 2007; 178:3143.
  46. Mishra BB, Moura-Alves P, Sonawane A, et al. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome. Cell Microbiol 2010; 12:1046.
  47. Chan J, Xing Y, Magliozzo RS, Bloom BR. Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. J Exp Med 1992; 175:1111.
  48. Chan J, Tanaka K, Carroll D, et al. Effects of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis. Infect Immun 1995; 63:736.
  49. MacMicking JD, North RJ, LaCourse R, et al. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci U S A 1997; 94:5243.
  50. Cooper AM, Dalton DK, Stewart TA, et al. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med 1993; 178:2243.
  51. Nicholson S, Bonecini-Almeida Mda G, Lapa e Silva JR, et al. Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med 1996; 183:2293.
  52. Nozaki Y, Hasegawa Y, Ichiyama S, et al. Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages. Infect Immun 1997; 65:3644.
  53. Wang CH, Liu CY, Lin HC, et al. Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages. Eur Respir J 1998; 11:809.
  54. Friedman CR, Quinn GC, Kreiswirth BN, et al. Widespread dissemination of a drug-susceptible strain of Mycobacterium tuberculosis. J Infect Dis 1997; 176:478.
  55. Ehrt S, Shiloh MU, Ruan J, et al. A novel antioxidant gene from Mycobacterium tuberculosis. J Exp Med 1997; 186:1885.
  56. Chen L, Xie QW, Nathan C. Alkyl hydroperoxide reductase subunit C (AhpC) protects bacterial and human cells against reactive nitrogen intermediates. Mol Cell 1998; 1:795.
  57. Bryk R, Griffin P, Nathan C. Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 2000; 407:211.
  58. St John G, Brot N, Ruan J, et al. Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates. Proc Natl Acad Sci U S A 2001; 98:9901.
  59. Ruan J, St John G, Ehrt S, et al. noxR3, a novel gene from Mycobacterium tuberculosis, protects Salmonella typhimurium from nitrosative and oxidative stress. Infect Immun 1999; 67:3276.
  60. Douvas GS, Looker DL, Vatter AE, Crowle AJ. Gamma interferon activates human macrophages to become tumoricidal and leishmanicidal but enhances replication of macrophage-associated mycobacteria. Infect Immun 1985; 50:1.
  61. Rook GA, Steele J, Fraher L, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986; 57:159.
  62. Rockett KA, Brookes R, Udalova I, et al. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 1998; 66:5314.
  63. Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003; 3:148.
  64. Long R, Gardam M. Tumour necrosis factor-alpha inhibitors and the reactivation of latent tuberculosis infection. CMAJ 2003; 168:1153.
  65. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098.
  66. Mohan VP, Scanga CA, Yu K, et al. Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology. Infect Immun 2001; 69:1847.
  67. Flynn JL, Goldstein MM, Chan J, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995; 2:561.
  68. Bean AG, Roach DR, Briscoe H, et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 1999; 162:3504.
  69. North RJ. Mice incapable of making IL-4 or IL-10 display normal resistance to infection with Mycobacterium tuberculosis. Clin Exp Immunol 1998; 113:55.
  70. Hirsch CS, Ellner JJ, Blinkhorn R, Toossi Z. In vitro restoration of T cell responses in tuberculosis and augmentation of monocyte effector function against Mycobacterium tuberculosis by natural inhibitors of transforming growth factor beta. Proc Natl Acad Sci U S A 1997; 94:3926.
  71. Vromman F, Subtil A. Exploitation of host lipids by bacteria. Curr Opin Microbiol 2014; 17:38.
  72. Salamon H, Bruiners N, Lakehal K, et al. Cutting edge: Vitamin D regulates lipid metabolism in Mycobacterium tuberculosis infection. J Immunol 2014; 193:30.
  73. Boussiotis VA, Tsai EY, Yunis EJ, et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest 2000; 105:1317.
  74. McKinney JD, Jacobs WR, Bloom BR. Persisting problems in tuberculosis. In: Emerging Infections, Krause RM (Ed), Academic Press, San Diego 1998.
  75. Andersen P, Munk ME, Pollock JM, Doherty TM. Specific immune-based diagnosis of tuberculosis. Lancet 2000; 356:1099.
  76. Barnes PF. Diagnosing latent tuberculosis infection: turning glitter to gold. Am J Respir Crit Care Med 2004; 170:5.
  77. Dockrell HM, Weir RE. Whole blood cytokine assays--a new generation of diagnostic tests for tuberculosis? Int J Tuberc Lung Dis 1998; 2:441.
  78. Lalvani A. Spotting latent infection: the path to better tuberculosis control. Thorax 2003; 58:916.
  79. Lein AD, Von Reyn CF. In vitro cellular and cytokine responses to mycobacterial antigens: application to diagnosis of tuberculosis infection and assessment of response to mycobacterial vaccines. Am J Med Sci 1997; 313:364.
  80. Lefford MJ. Transfer of adoptive immunity to tuberculosis in mice. Infect Immun 1975; 11:1174.
  81. Orme IM, Collins FM. Protection against Mycobacterium tuberculosis infection by adoptive immunotherapy. Requirement for T cell-deficient recipients. J Exp Med 1983; 158:74.
  82. Pedrazzini T, Louis JA. Functional analysis in vitro and in vivo of Mycobacterium bovis strain BCG-specific T cell clones. J Immunol 1986; 136:1828.
  83. Orme IM. The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. J Immunol 1987; 138:293.
  84. Caruso AM, Serbina N, Klein E, et al. Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. J Immunol 1999; 162:5407.
  85. Oddo M, Renno T, Attinger A, et al. Fas ligand-induced apoptosis of infected human macrophages reduces the viability of intracellular Mycobacterium tuberculosis. J Immunol 1998; 160:5448.
  86. Stenger S, Mazzaccaro RJ, Uyemura K, et al. Differential effects of cytolytic T cell subsets on intracellular infection. Science 1997; 276:1684.
  87. Flynn JL, Goldstein MM, Triebold KJ, et al. Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc Natl Acad Sci U S A 1992; 89:12013.
  88. Sousa AO, Mazzaccaro RJ, Russell RG, et al. Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice. Proc Natl Acad Sci U S A 2000; 97:4204.
  89. Skinner MA, Yuan S, Prestidge R, et al. Immunization with heat-killed Mycobacterium vaccae stimulates CD8+ cytotoxic T cells specific for macrophages infected with Mycobacterium tuberculosis. Infect Immun 1997; 65:4525.
  90. Turner J, Dockrell HM. Stimulation of human peripheral blood mononuclear cells with live Mycobacterium bovis BCG activates cytolytic CD8+ T cells in vitro. Immunology 1996; 87:339.
  91. Beckman EM, Porcelli SA, Morita CT, et al. Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells. Nature 1994; 372:691.
  92. Kägi D, Vignaux F, Ledermann B, et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 1994; 265:528.
  93. Lowin B, Hahne M, Mattmann C, Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 1994; 370:650.
  94. Cooper AM, D'Souza C, Frank AA, Orme IM. The course of Mycobacterium tuberculosis infection in the lungs of mice lacking expression of either perforin- or granzyme-mediated cytolytic mechanisms. Infect Immun 1997; 65:1317.
  95. Laochumroonvorapong P, Wang J, Liu CC, et al. Perforin, a cytotoxic molecule which mediates cell necrosis, is not required for the early control of mycobacterial infection in mice. Infect Immun 1997; 65:127.
  96. Stenger S, Hanson DA, Teitelbaum R, et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 1998; 282:121.
  97. Rosat JP, Grant EP, Beckman EM, et al. CD1-restricted microbial lipid antigen-specific recognition found in the CD8+ alpha beta T cell pool. J Immunol 1999; 162:366.
  98. Senaratne RH, De Silva AD, Williams SJ, et al. 5'-Adenosinephosphosulphate reductase (CysH) protects Mycobacterium tuberculosis against free radicals during chronic infection phase in mice. Mol Microbiol 2006; 59:1744.
  99. Orme IM, Cooper AM. Cytokine/chemokine cascades in immunity to tuberculosis. Immunol Today 1999; 20:307.
  100. Rhoades ER, Cooper AM, Orme IM. Chemokine response in mice infected with Mycobacterium tuberculosis. Infect Immun 1995; 63:3871.
  101. Fraziano M, Cappelli G, Santucci M, et al. Expression of CCR5 is increased in human monocyte-derived macrophages and alveolar macrophages in the course of in vivo and in vitro Mycobacterium tuberculosis infection. AIDS Res Hum Retroviruses 1999; 15:869.
  102. Peters W, Scott HM, Chambers HF, et al. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 2001; 98:7958.
  103. Lu B, Rutledge BJ, Gu L, et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 1998; 187:601.
  104. Shimono N, Morici L, Casali N, et al. Hypervirulent mutant of Mycobacterium tuberculosis resulting from disruption of the mce1 operon. Proc Natl Acad Sci U S A 2003; 100:15918.
  105. Chitale S, Ehrt S, Kawamura I, et al. Recombinant Mycobacterium tuberculosis protein associated with mammalian cell entry. Cell Microbiol 2001; 3:247.
  106. Queiroz A, Medina-Cleghorn D, Marjanovic O, et al. Comparative metabolic profiling of mce1 operon mutant vs wild-type Mycobacterium tuberculosis strains. Pathog Dis 2015; 73:ftv066.
  107. Rao V, Gao F, Chen B, et al. Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis -induced inflammation and virulence. J Clin Invest 2006; 116:1660.
  108. Glatman-Freedman A, Casadevall A. Serum therapy for tuberculosis revisited: reappraisal of the role of antibody-mediated immunity against Mycobacterium tuberculosis. Clin Microbiol Rev 1998; 11:514.
  109. Vordermeier HM, Venkataprasad N, Harris DP, Ivanyi J. Increase of tuberculous infection in the organs of B cell-deficient mice. Clin Exp Immunol 1996; 106:312.
  111. BLOCH H. Studies on the virulence of tubercle bacilli; isolation and biological properties of a constituent of virulent organisms. J Exp Med 1950; 91:197.
  112. NOLL H, BLOCH H, ASSELINEAU J, LEDERER E. The chemical structure of the cord factor of Mycobacterium tuberculosis. Biochim Biophys Acta 1956; 20:299.
  113. Brennan PJ, Nikaido H. The envelope of mycobacteria. Annu Rev Biochem 1995; 64:29.
  114. Barry CE 3rd, Lee RE, Mdluli K, et al. Mycolic acids: structure, biosynthesis and physiological functions. Prog Lipid Res 1998; 37:143.
  115. Yuan Y, Zhu Y, Crane DD, Barry CE 3rd. The effect of oxygenated mycolic acid composition on cell wall function and macrophage growth in Mycobacterium tuberculosis. Mol Microbiol 1998; 29:1449.
  116. Dubnau E, Chan J, Raynaud C, et al. Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol Microbiol 2000; 36:630.
  117. Glickman MS, Cox JS, Jacobs WR Jr. A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell 2000; 5:717.
  118. Cox JS, Chen B, McNeil M, Jacobs WR Jr. Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 1999; 402:79.
  119. Rousseau C, Sirakova TD, Dubey VS, et al. Virulence attenuation of two Mas-like polyketide synthase mutants of Mycobacterium tuberculosis. Microbiology 2003; 149:1837.
  120. Sulzenbacher G, Canaan S, Bordat Y, et al. LppX is a lipoprotein required for the translocation of phthiocerol dimycocerosates to the surface of Mycobacterium tuberculosis. EMBO J 2006; 25:1436.
  121. Ojha AK, Baughn AD, Sambandan D, et al. Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol 2008; 69:164.
  122. Uchida Y, Casali N, White A, et al. Accelerated immunopathological response of mice infected with Mycobacterium tuberculosis disrupted in the mce1 operon negative transcriptional regulator. Cell Microbiol 2007; 9:1275.
  123. Cantrell SA, Leavell MD, Marjanovic O, et al. Free mycolic acid accumulation in the cell wall of the mce1 operon mutant strain of Mycobacterium tuberculosis. J Microbiol 2013; 51:619.
  124. Forrellad MA, McNeil M, Santangelo Mde L, et al. Role of the Mce1 transporter in the lipid homeostasis of Mycobacterium tuberculosis. Tuberculosis (Edinb) 2014; 94:170.
  125. Valway SE, Sanchez MP, Shinnick TF, et al. An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N Engl J Med 1998; 338:633.
  126. Manca C, Tsenova L, Barry CE 3rd, et al. Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo and in vitro, but is not more virulent than other clinical isolates. J Immunol 1999; 162:6740.
  127. Reed MB, Domenech P, Manca C, et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 2004; 431:84.
  128. Constant P, Perez E, Malaga W, et al. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J Biol Chem 2002; 277:38148.
  129. Sinsimer D, Huet G, Manca C, et al. The phenolic glycolipid of Mycobacterium tuberculosis differentially modulates the early host cytokine response but does not in itself confer hypervirulence. Infect Immun 2008; 76:3027.
  130. Brennan MJ, Thole J. Tuberculosis vaccines: a strategic blueprint for the next decade. Tuberculosis (Edinb) 2012; 92 Suppl 1:S6.
  131. Sander CR, Pathan AA, Beveridge NE, et al. Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individuals. Am J Respir Crit Care Med 2009; 179:724.
  132. Hawkridge T, Scriba TJ, Gelderbloem S, et al. Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa. J Infect Dis 2008; 198:544.
  133. Tameris MD, Hatherill M, Landry BS, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013; 381:1021.
  134. Abel B, Tameris M, Mansoor N, et al. The novel tuberculosis vaccine, AERAS-402, induces robust and polyfunctional CD4+ and CD8+ T cells in adults. Am J Respir Crit Care Med 2010; 181:1407.
  135. Hawkridge T, Mahomed H. Prospects for a new, safer and more effective TB vaccine. Paediatr Respir Rev 2011; 12:46.
  136. Aagaard C, Hoang T, Dietrich J, et al. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat Med 2011; 17:189.
  137. Miyata T, Cheigh CI, Casali N, et al. An adjunctive therapeutic vaccine against reactivation and post-treatment relapse tuberculosis. Vaccine 2012; 30:459.