Jeyanathan, Mangalakumari; (2002) Persistence of mycobacterium tuberculosis in people without clinical disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mycobacterium tuberculosis (MTB) can cause both active disease and latent tuberculosis (LTBI). Latent infection can reactivate and, is therefore, a potential reservoir of infection. Effective diagnosis and treatment of LTBI can only be achieved with a clear understanding of the pathogenesis of LTBI. This thesis attempts to develop an effective diagnostic method to detect LTBI and to clarify some aspects of its pathogenesis. Tuberculin skin tests performed on Sri Lankan school children revealed a high prevalence of LTBI (40.5%) in Jaffna compared to Hambanthota (7.3%). Geographical variations and dietary habits of the population in the two locations have influenced reactions to tuberculin significantly. Evaluation of antibody titre against 16kDa, 38kDa, 65kDa, 70kDa antigens using ELISA revealed a significantly increased IgG response in elderly people. Titres to 16kDa and 38kDa antigens were as high as in people with active disease. However, isoelectric focusing revealed that the antibody response in elderly people was mainly oligoclonal to 16kDa whereas the oligoclonal response in active disease was mainly to the 38kDa antigen. Polymerase chain reaction (PCR) detected MTB DNA in the sputum of 55% of elderly people, suggesting shedding of bacilli during LTBI. However, spoligotyping of the DNA ruled out transmission of infection within this community. Detection of MTB DNA using PCR and in situ PCR on autopsy material of people without clinical TB suggests that MTB can lurk in arrested granulomas and in normal tissues during LTBI. Latency was maintained at various extrapulmonary sites including the brain. MTB DNA was detected in the cytoplasm, and less frequently inside the nucleus of non-professional phagocytic cells and in macrophages. Acid-fast and immunohistochemical staining failed to detect bacilli in sections adjacent to those that were MTB DNA positive. Spoligotyping of MTB DNA in these tissues revealed a conserved pattern. In conclusion, this study has made some interesting findings, but raised many questions regarding the LTBI pathogenesis. Addressing these may help the development of effective diagnosis and treatment for LTBI.

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