Latency in Pulmonary Tuberculosis

Summary

The immune responses in latent tuberculosis are poorly understood. While it is difficult to define the onset of latency during natural infection, patients undergoing treatment for tuberculosis are driven into a state of latency or cure. The present study on the effect of 3 and 4 month regimens containing moxifloxacin in sputum smear and culture positive pulmonary tuberculosis (TRC Study number 24) offers us the opportunity to study definitive immune responses pre and post treatment. We will evaluate a variety of innate and adaptive immune responses in patients before and after treatment and our study will compare the differences in immuno-phenotype (eg. Markers of T, B and NK cell activation, proliferation and regulatory phenotype) and function (eg. Production of cytokines, proliferative responses to TB antigens) at different time points following treatment. In addition, since a small percentage of patients will undergo relapse following treatment, the kinetics of immune responses in these patients will used to assess immunological predictors of relapse in tuberculosis.

Timeline

Start

2010-02

Primary completion

2015-12

Completion

2016-07

Publications

• Background Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol. 1974 Feb;99(2):131-8. doi: 10.1093/oxfordjournals.aje.a121593. No abstract available.
• Background Lillebaek T, Dirksen A, Baess I, Strunge B, Thomsen VO, Andersen AB. Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection. J Infect Dis. 2002 Feb 1;185(3):401-4. doi: 10.1086/338342. Epub 2002 Jan 17.
• Background Wayne LG, Sohaskey CD. Nonreplicating persistence of mycobacterium tuberculosis. Annu Rev Microbiol. 2001;55:139-63. doi: 10.1146/annurev.micro.55.1.139.
• Background EDWARDS PQ, EDWADS LB. Story of the tuberculin test from an epidemiologic viewpoint. Am Rev Respir Dis. 1960 Jan;81(1)Pt 2:1-47. No abstract available.
• Background Kaufmann SH. How can immunology contribute to the control of tuberculosis? Nat Rev Immunol. 2001 Oct;1(1):20-30. doi: 10.1038/35095558.
• Background Lin MY, Ottenhoff TH. Not to wake a sleeping giant: new insights into host-pathogen interactions identify new targets for vaccination against latent Mycobacterium tuberculosis infection. Biol Chem. 2008 May;389(5):497-511. doi: 10.1515/bc.2008.057.
• Background Ulrichs T, Kaufmann SH. New insights into the function of granulomas in human tuberculosis. J Pathol. 2006 Jan;208(2):261-9. doi: 10.1002/path.1906.
• Background Khader SA, Cooper AM. IL-23 and IL-17 in tuberculosis. Cytokine. 2008 Feb;41(2):79-83. doi: 10.1016/j.cyto.2007.11.022. Epub 2008 Jan 22.
• Background North RJ, Jung YJ. Immunity to tuberculosis. Annu Rev Immunol. 2004;22:599-623. doi: 10.1146/annurev.immunol.22.012703.104635.
• Background Locht C, Rouanet C, Hougardy JM, Mascart F. How a different look at latency can help to develop novel diagnostics and vaccines against tuberculosis. Expert Opin Biol Ther. 2007 Nov;7(11):1665-77. doi: 10.1517/14712598.7.11.1665.
• Background Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol. 2002 Dec;2(12):933-44. doi: 10.1038/nri954.
• Background Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008 May;8(5):337-48. doi: 10.1038/nri2295.
• Background McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity. 2008 Apr;28(4):445-53. doi: 10.1016/j.immuni.2008.03.001.
• Background Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821-52. doi: 10.1146/annurev.immunol.25.022106.141557.
• Background Fontenot JD, Rudensky AY. Molecular aspects of regulatory T cell development. Semin Immunol. 2004 Apr;16(2):73-80. doi: 10.1016/j.smim.2003.12.002.
• Background Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531-62. doi: 10.1146/annurev.immunol.21.120601.141122.
• Background Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-48. doi: 10.1146/annurev.immunol.23.021704.115611.
• Background Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity. 2008 Apr;28(4):468-76. doi: 10.1016/j.immuni.2008.03.003.
• Kumar NP, Moideen K, Dhakshinraj SD, Banurekha VV, Nair D, Dolla C, Kumaran P, Babu S. Profiling leucocyte subsets in tuberculosis-diabetes co-morbidity. Immunology. 2015 Oct;146(2):243-50. doi: 10.1111/imm.12496. Epub 2015 Jul 6.
• Kumar NP, Sridhar R, Nair D, Banurekha VV, Nutman TB, Babu S. Type 2 diabetes mellitus is associated with altered CD8(+) T and natural killer cell function in pulmonary tuberculosis. Immunology. 2015 Apr;144(4):677-86. doi: 10.1111/imm.12421.

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