| Summary: | Bibliography: leaves 122-138. === Exposure to Mycobacterium tuberculosis results in clinical tuberculosis only in a small percentage of immunocompetent individuals. In most instances mycobacteria are controlled by the host immune system and survive in a dormant state within granuloma. lmmunosuppression, however, may result in reactivation of active tuberculosis resulting in clinical disease. Using low dose aerosol infection of M. tuberculosis in mice, a short-duration model of rifampicin-isoniazid (RMP-INH)-induced persistent tuberculosis is described. This persistent infection is characterised by undetectable levels of colony-forming units (CFU) in mouse organs and mice being clinically asymptomatic for prolonged periods. Reactivation of persistent tuberculosis can occur spontaneously following short-course chemotherapy or can be achieved by immunosuppression, specifically inhibition of macrophage- specific nitric oxide synthase (NOS2) by a chemical inhibitor, aminoguanidine. This model can therefore be used to characterise spontaneous or drug-induced reactivation of murine tuberculosis, as this is not feasible to study in human subjects. Additionally, this model may serve as a valuable tool for testing novel vaccines and antituberculous drugs, especially those designed to combat persistent infection. Mycobacterial genome copy enumeration and assessment of 168 ribosomal RNA (168 rRNA) and sigma factor A (sigA) gene expression revealed that large numbers of dormant bacilli are present in lung tissue during the persistent phase of infection in this model. This finding opens up the possibility that additional gene expression profiles can be analysed with current technology, unravelling the exact metabolic status of these dormant mycobacteria. Moreover, this model facilitates characterisation of another poorly understood aspect, namely reinfection. Preliminary aerosol reinfection during the persistent phase of tuberculosis revealed that the primary- infected dormant M. tuberculosis strain may be reactivated and may outgrow the primary strain during reinfection. Tumour necrosis factor (TNF) deficient mice are known to be highly susceptible to M. tuberculosis infection. In this study it was asked whether TNF is required for post-infectious immunity in aerosol-infected mice. This model was applied and mice were treated with RlV|P-INH for 4 weeks to reduce the CFU to undetectable levels. While wild-type control mice spontaneously reactivated but controlled the infection upon cessation of chemotherapy, TNF deficient mice developed fatal reactivation of infection. The increased susceptibility of TNF deficient mice was accompanied by diminished recruitment and activation of T cells and macrophages into the lung with defective granuloma formation and reduced inducible nitric oxide synthase expression. Reduced chemokine production in the lung might explain sub-optimal recruitment and activation of T cells and uncontrolled infection. Therefore, despite a massive reduction of the mycobacterial load by chemotherapy, TNF deficient mice were unable to compensate and mount a protective immune response. In conclusion, endogenous TNF is critical to maintain latent tuberculosis infection and in its absence no specific immunity is generated.
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