Opinion | Published:

Advancing host-directed therapy for tuberculosis

Nature Reviews Immunology volume 15, pages 255263 (2015) | Download Citation

This article has been updated


Improved treatments are needed for nearly all forms of Mycobacterium tuberculosis infection. Adjunctive host-directed therapies have the potential to shorten tuberculosis treatment duration, prevent resistance and reduce lung injury by promoting autophagy, antimicrobial peptide production and other macrophage effector mechanisms, as well as by modifying specific mechanisms that cause lung inflammation and matrix destruction. The range of candidates is broad, including several agents approved for other clinical indications that are ready for evaluation in Phase II clinical trials. The promise of new and existing host-directed therapies that could accelerate response and improve tuberculosis treatment outcomes is discussed in this Opinion article.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Change history

  • 17 March 2015

    In the version of this article that was originally published online, some of the information in the acknowledgements section was incorrect. This has been corrected online and was corrected for the print version of the article.


  1. 1.

    et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N. Engl. J. Med. 371, 1577–1587 (2014).

  2. 2.

    et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N. Engl. J. Med. 371, 1588–1598 (2014).

  3. 3.

    et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N. Engl. J. Med. 371, 1599–1608 (2014).

  4. 4.

    et al. A trial of mass isoniazid preventive therapy for tuberculosis control. N. Engl. J. Med. 370, 301–310 (2014).

  5. 5.

    et al. Pulmonary impairment after tuberculosis and its contribution to TB burden. BMC Public Health 10, 259 (2010).

  6. 6.

    & The after-history of pulmonary tuberculosis. VI. The first fifteen years following diagnosis. Am. Rev. Respir. Dis. 81, 839–849 (1960).

  7. 7.

    et al. Interaction of pattern recognition receptors with Mycobacterium tuberculosis. J. Clin. Immunol. 35, 1–10 (2015).

  8. 8.

    , & Macrophages in tuberculosis: friend or foe. Semin. Immunopathol. 35, 563–583 (2013).

  9. 9.

    et al. Macrophages acquire neutrophil granules for antimicrobial activity against intracellular pathogens. J. Immunol. 177, 1864–1871 (2006).

  10. 10.

    et al. S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am. J. Respir. Crit. Care Med. 188, 1137–1146 (2013).

  11. 11.

    et al. Clinical and epidemiological characteristics of individuals resistant to M. tuberculosis infection in a longitudinal TB household contact study in Kampala, Uganda. BMC Infect. Dis. 14, 352 (2014).

  12. 12.

    et al. Early innate immunity determines outcome of Mycobacterium tuberculosis pulmonary infection in rabbits. Cell Commun. Signal. 11, 60 (2013).

  13. 13.

    , , & Novel STAT1 alleles in a patient with impaired resistance to mycobacteria. J. Clin. Immunol. 31, 265–271 (2011).

  14. 14.

    et al. A mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med. 335, 1941–1949 (1996).

  15. 15.

    et al. Failure to control growth of mycobacteria in blood from children infected with human immunodeficiency virus, and its relationship to T cell function. J. Infect. Dis. 187, 1544–1551 (2003).

  16. 16.

    et al. Inhibition of mycobacterial growth in vitro is enhanced following primary BCG vaccination but not BCG revaccination of human subjects. Clin. Vaccine Immunol. 20, 1683–1689 (2013).

  17. 17.

    & Letting sleeping dos lie: does dormancy play a role in tuberculosis? Annu. Rev. Microbiol. 64, 293–311 (2010).

  18. 18.

    et al. Appropriate DevR (DosR)-mediated signaling determines transcriptional response, hypoxic viability and virulence of Mycobacterium tuberculosis. PLoS ONE 7, e35847 (2012).

  19. 19.

    , , , & Longevity loss among cured tuberculosis patients and the potential value of prevention. Int. J. Tuberc. Lung Dis. 18, 1347–1352 (2014).

  20. 20.

    et al. Assessment of long term status of sputum positive pulmonary TB patients successfully treated with short course chemotherapy. Indian J. Tuberc. 56, 132–140 (2009).

  21. 21.

    , , & Mycobacterial lipoarabinomannan and related lipoglycans: from biogenesis to modulation of the immune response. Mol. Microbiol. 53, 391–403 (2004).

  22. 22.

    et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).

  23. 23.

    , , & Role of autophagy in the host response to microbial infection and potential for therapy. Curr. Opin. Immunol. 23, 65–70 (2011).

  24. 24.

    , & Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150, 803–815 (2012).

  25. 25.

    et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 121, 3554–3563 (2011).

  26. 26.

    et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004).

  27. 27.

    et al. Structure–function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA. Cell 154, 748–762 (2013).

  28. 28.

    et al. Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Br. J. Cancer 108, 1306–1315 (2013).

  29. 29.

    et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013).

  30. 30.

    et al. Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth. PLoS Pathog. 10, e1003946 (2014).

  31. 31.

    et al. Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages. J. Immunol. 189, 4069–4078 (2012).

  32. 32.

    et al. Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis. Cell Host Microbe 10, 475–485 (2011).

  33. 33.

    & Abl kinases regulate autophagy by promoting the trafficking and function of lysosomal components. J. Biol. Chem. 283, 35941–35953 (2008).

  34. 34.

    et al. Large-scale imatinib dose–concentration–effect study in CML patients under routine care conditions. Leuk. Res. 38, 764–772 (2014).

  35. 35.

    et al. The protein kinase double-stranded RNA-dependent (PKR) enhances protection against disease cause by a non-viral pathogen. PLoS Pathog. 9, e1003557 (2013).

  36. 36.

    et al. Improved control of tuberculosis and activation of macrophages in mice lacking protein kinase R. PLoS ONE 7, e30512 (2012).

  37. 37.

    et al. Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa. Proc. Natl Acad. Sci. USA 108, 19013–19017 (2011).

  38. 38.

    et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

  39. 39.

    et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 179, 843–850 (2009).

  40. 40.

    , & The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med. Indones. 38, 3–5 (2006).

  41. 41.

    et al. L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial. PLoS ONE 8, e70032 (2013).

  42. 42.

    et al. High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 377, 242–250 (2011).

  43. 43.

    et al. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc. Natl Acad. Sci. USA 109, 15449–15454 (2012).

  44. 44.

    et al. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am. J. Clin. Nutr. 75, 720–727 (2002).

  45. 45.

    et al. Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator. J. Cell Biol. 169, 93–104 (2005).

  46. 46.

    , , & Phenylbutyrate induces antimicrobial peptide expression. Antimicrob. Agents Chemother. 53, 5127–5133 (2009).

  47. 47.

    , , , & Vitamin D3 and phenylbutyrate promote development of a human dendritic cell subset displaying enhanced antimicrobial properties. J. Leukoc. Biol. 95, 883–891 (2014).

  48. 48.

    et al. Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis. BMC Pulm. Med. 13, 23 (2013).

  49. 49.

    et al. Clinical trial of oral phenylbutyrate and vitamin D adjunctive therapy in pulmonary tuberculosis in Bangladesh. Int. J. Tuberc. Lung Dis. 18, S233–S234 (2014).

  50. 50.

    et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

  51. 51.

    et al. Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro. J. Pharmacol. Exp. Ther. 334, 206–213 (2010).

  52. 52.

    et al. Metformin as adjunct anti-tuberculosis therapy. Sci. Transl Med. 6, 263ra159 (2014).

  53. 53.

    et al. Immunomodulation with recombinant interferon-γ1b in pulmonary tuberculosis. PLoS ONE 4, e6984 (2009).

  54. 54.

    et al. Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis. Am. J. Respir. Crit. Care Med. 168, 185–191 (2003).

  55. 55.

    & Antibody-mediated immunity against tuberculosis: implications for vaccine development. Cell Host Microbe 13, 250–262 (2013).

  56. 56.

    et al. Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice. Infect. Immun. 73, 6101–6109 (2005).

  57. 57.

    , & Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin. Infect. Dis. 25, 872–887 (1997).

  58. 58.

    , , & Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis. Lancet Infect. Dis. 13, 223–237 (2013).

  59. 59.

    et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148, 434–446 (2012).

  60. 60.

    Corticosteroid effects on sputum culture in pulmonary tuberculosis: a meta-regression analysis. Open Forum Infect. Dis. (2014).

  61. 61.

    , , & Month 2 culture status and treatment duration as predictors of tuberculosis relapse risk in a meta-regression model. PLoS ONE 8, e71116 (2013).

  62. 62.

    , , , & Corticosteroids in pulmonary tuberculosis. I. Over-all results in Madison–Minneapolis veterans administration hospitals steroid study. Am. Rev. Respir. Dis. 92, 376–391 (1965).

  63. 63.

    et al. Immunoadjuvant therapy for HIV-associated tuberculosis with prednisolone: a phase II clinical trial in Uganda. J. Infect. Dis. 191, 856–865 (2005).

  64. 64.

    et al. Study of chemotherapy regimens of 5 and 7 months' duration and the role of corticosteroids in the treatment of sputum-positive patients with pulmonary tuberculosis in South India. Tubercle 64, 73–91 (1983).

  65. 65.

    et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001).

  66. 66.

    , & The potential for disease modification in Crohn's disease. Nature Rev. Gastroenterol. Hepatol. 7, 79–85 (2010).

  67. 67.

    et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 50, 1400–1411 (2004).

  68. 68.

    et al. A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis. AIDS 18, 257–264 (2004).

  69. 69.

    et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121, 1088–1094 (2001).

  70. 70.

    et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 124, 177–185 (2003).

  71. 71.

    Mathematical modeling of the cause of tuberculosis during tumor necrosis factor blockade. Arthritis Rheum. 58, 947–952 (2008).

  72. 72.

    , , & Granulomatous infections due to tumor necrosis factor blockade: correction. Clin. Infect. Dis. 39, 1254–1256 (2004).

  73. 73.

    , , & Glucocorticoid use, other associated factors, and the risk of tuberculosis. Arthritis Rheum. 55, 19–26 (2006).

  74. 74.

    et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum. 52, 1766–1772 (2005).

  75. 75.

    et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 60, 1884–1894 (2009).

  76. 76.

    , , & Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction involving the brain, lung, and lymph nodes. Clin. Infect. Dis. 47, e79–e82 (2008).

  77. 77.

    et al. Anti-TNF therapy for severe CNS tuberculosis causing blindness. Eur. Conf. Clin. Micro. Infect. Dis. , (2013).

  78. 78.

    , & Adalimumab treatment of life-threatening tuberculosis. Clin. Infect. Dis. 48, 1429–1432 (2009).

  79. 79.

    et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 1451–1459 (2002).

  80. 80.

    et al. Risk of tuberculosis reactivation with tofacitinib (CP-690550). J. Infect. Dis. 205, 1705–1708 (2012).

  81. 81.

    et al. Tuberculosis and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheum. Abstr. 64 (Suppl. 10), 1278 (2012).

  82. 82.

    Thalidomide in the treatment of lepra reactions. Clin. Pharmacol. Ther. 6, 303–306 (1965).

  83. 83.

    , , , & Thalidomide selectively inhibits tumor necrosis factor α production by stimulated human monocytes. J. Exp. Med. 173, 699–703 (1991).

  84. 84.

    , & , , & Tuberculous meningitis-related optic neuritis: recovery of vision with thalidomide in 4 consecutive cases. J. Child Neurol. 25, 822–828 (2010).

  85. 85.

    , , , & Intractable intracranial tuberculous infection responsive to thalidomide: report of four cases. J. Child Neurol. 21, 301–308 (2006).

  86. 86.

    et al. Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. J. Child Neurol. 19, 250–257 (2004).

  87. 87.

    et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010).

  88. 88.

    et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2014).

  89. 89.

    et al. Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro. Proc. Natl Acad. Sci. USA 110, 12703–12708 (2013).

  90. 90.

    et al. Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice. PLoS ONE 6, e17091 (2011).

  91. 91.

    et al. Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs. PLoS Pathog. 7, e1002262 (2011).

  92. 92.

    et al. Adjuvant host-directed therapy with types 3 and 5 but not type 4 phosphodiesterase inhibitors shortens the duration of tuberculosis treatment. J. Infect. Dis. 208, 512–519 (2013).

  93. 93.

    et al. Successful shortening of tuberculosis treatment using adjuvant host-directed therapy with FDA-approved phosphodiesterase inhibitors in the mouse model. PLoS ONE 7, e30749 (2012).

  94. 94.

    , , , & Pentoxifylline treatment of mice with chronic pulmonary tuberculosis accelerates the development of destructive pathology. Immunology 102, 248–253 (2001).

  95. 95.

    et al. Pentoxifylline in human immunodeficiency virus-seropositive tuberculosis: a randomized, controlled trial. J. Infect. Dis. 174, 727–733 (1996).

  96. 96.

    et al. Pentoxifylline in human immunodeficiency virus–positive tuberculosis: safety at 4 years. J. Infect. Dis. 178, 1861 (1998).

  97. 97.

    et al. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature 511, 99–103 (2014).

  98. 98.

    et al. Increased release of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis. Am. J. Respir. Crit. Care Med. 153, 799–804 (1996).

  99. 99.

    , , & Increased interleukin-1 production and monocyte suppressor cell activity associated with human tuberculosis. Am. Rev. Respir. Dis. 133, 73–77 (1986).

  100. 100.

    Assessment of serum IL-1, IL-2 and IFN-γ levels in untreated pulmonary tuberculosis patients: role in pathogenesis. Arch. Med. Res. 42, 199–201 (2011).

  101. 101.

    , & Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis. J. Antimicrob. Chemother. 59, 313–316 (2007).

  102. 102.

    et al. Ibuprofen therapy resulted in significantly decreased tissue bacillary loads and increased survival in a new murine experimental model of active tuberculosis. J. Infect. Dis. 208, 199–202 (2013).

  103. 103.

    , , & Pharmacological modulation of TNF production in macrophages. J. Microbiol. Immunol. Infect. 37, 8–15 (2004).

  104. 104.

    & Recent development in pleiotropic effects of statins on cardiovascular disease through regulation of transforming growth factor-beta superfamily. Cytokine Growth Factor Rev. 22, 167–175 (2011).

  105. 105.

    et al. Statin therapy reduces the Mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation. J. Infect. Dis. 209, 754–763 (2014).

  106. 106.

    et al. Simvastatin increases the in vivo activity of the first-line tuberculosis regimen. J. Antimicrob. Chemother. 69, 2453–2457 (2014).

  107. 107.

    et al. The effects of statin use on the development of tuberculosis among patients with diabetes mellitus. Int. J. Tuberc. Lung Dis. 18, 717–724 (2014).

  108. 108.

    et al. Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor γ linking mannose receptor recognition to regulation of immune responses. J. Immunol. 185, 929–942 (2010).

  109. 109.

    , , , & Serum MMPs 7–9 and their inhibitors during glucocorticoid and anti-TNF-α therapy in pediatric inflammatory bowel disease. Scand. J. Gastroenterol. 47, 785–794 (2012).

  110. 110.

    & Clinical studies on the management of periodontal diseases utilizing subantimicrobial dose doxycycline (SDD). Pharmacol. Res. 63, 114–120 (2011).

  111. 111.

    et al. Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases. Am. J. Respir. Crit. Care Med. 185, 989–997 (2012).

  112. 112.

    et al. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir. Med. 2, 108–122 (2014).

  113. 113.

    et al. PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. Sci. Transl Med. 6, 265ra167 (2014).

  114. 114.

    et al. PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis. Sci. Transl Med. 6, 265ra166 (2014).

  115. 115.

    et al. Whole blood bactericidal activity during treatment of pulmonary tuberculosis. J. Infect. Dis. 187, 270–278 (2003).

  116. 116.

    & Chronic obstructive airways disease following treated pulmonary tuberculosis. Respir. Med. 83, 195–198 (1989).

  117. 117.

    et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am. Rev. Respir. Dis. 148, 1292–1297 (1993).

  118. 118.

    et al. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 358, 1687–1693 (2001).

  119. 119.

    et al. Recurrent TB: relapse or reinfection? The effect of HIV in a general population cohort in Malawi. AIDS 24, 417–426 (2010).

  120. 120.

    , & Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 359, 2059–2064 (2002).

  121. 121.

    et al. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am. J. Respir. Crit. Care Med. 151, 129–135 (1995).

  122. 122.

    et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N. Engl. J. Med. 362, 697–706 (2010).

Download references


The authors thank workshop participants for providing summaries of their presentations and the session chairs for their assistance in reviewing earlier versions of this document: L. S. Schlesinger (Ohio State University, USA), T. R. Hawn (University of Washington, USA), W. H. Boom (Case Western Reserve University, Ohio, USA), H. Kornfeld (University of Massachusetts, USA), G. Churchyard (Aurum Institute, South Africa), J. Ellner (Boston University, Massachusetts, USA) and G. Kaplan (Bill and Melinda Gates Foundation). They also acknowledge the editorial and administrative assistance of D. Johnson and S. Williams (Division of AIDS, US National Institute of Allergy and Infectious Disease (NIAID)). This publication and workshop have been funded in whole or in part with Federal funds from the Division of AIDS, NIAID, US National Institutes of Health, Department of Health and Human Services, under contract number HHSN272201200009C, entitled NIAID HIV and Other Infectious Diseases Clinical Research Support Services (CRSS).

Author information


  1. Aurum Institute, Johannesburg 2193, South Africa.

    • Robert S. Wallis
  2. Division of AIDS, National Institutes of Health, Bethesda, Maryland 20852, USA.

    • Richard Hafner


  1. Search for Robert S. Wallis in:

  2. Search for Richard Hafner in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert S. Wallis.



A cellular process that delivers potentially harmful cytosolic macromolecules and organelles to lysosomes for degradation. In macro-autophagy, an isolation membrane fuses with itself to enclose the pathogen to form an autophagosome, which can then fuse with lysosomes.

C3HeB/FeJ mice

A strain of mice (also known as Kramnik mice) that develops granulomatous lesions with central necrosis and hypoxia following Mycobacterium tuberculosis infection. By contrast, lesions in BALB/c mice are non-necrotic and lack hypoxia.


Organized collections of tightly apposed epithelioid macrophages, lymphocytes and fibroblasts, with or without necrotic centres.

Immune reconstitution inflammatory syndrome

(IRIS). Paradoxical reactions that occur during combined antimicrobial and antiretroviral treatment in individuals with tuberculosis and AIDS.


A molecular complex of several proteins that cleaves pro-interleukin-1 (IL-1) and pro-IL-18 following assembly, thereby producing active IL-1 and IL-18.

Latent M. tuberculosis infection

(LTBI). A clinical state in which there is evidence of T cell sensitization to Mycobacterium tuberculosis antigens (by tuberculin skin test or interferon-release assay) but no evidence of disease (by chest radiography and sputum culture). Individuals with LTBI are at risk of developing active tuberculosis if immunosuppressed by medical therapies or other infections.

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as the expression of cytokines and growth factors, in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphatidylinositol-3-OH kinase downstream of growth factors, as well as nutrients, such as amino acids, glucose and oxygen.

Paradoxical reactions

Exacerbation of clinical disease (worsened fever and increased lymph node and lung involvement) despite microbiological improvement (conversion of sputum cultures to negative) that occurs after antimicrobial treatment has commenced and is attributed to activation of inflammatory mechanisms.


A cytoplasmic body that is formed by the fusion of a phagosome (containing ingested particles at a neutral pH) and a lysosome (containing hydrolytic and other enzymes at an acidic pH). Fusion of the phagolysosome is inhibited by Mycobacterium tuberculosis as a mechanism for its intracellular survival.

S100 proteins

A family of low-molecular-weight proteins that participate in the inflammatory response by promoting leukocyte migration.

About this article

Publication history




Further reading