| Mycobacterium tuberculosis, the infectious agent of tuberculosis, remains a leading cause of infectious disease worldwide due to poor control of infection, multidrug-resistant strains, and more recently, co-infection with HIV. To facilitate the study of the pathogenesis of M. tuberculosis and the potential discovery of new drug targets, our laboratory makes use of the Mycobacterium marinum model of tuberculosis infection. M. marinum is a very close relative of M. tuberculosis that causes a chronic, granulomatous disease in fish with many similarities to tuberculosis infection in humans. Of importance to the pathogenesis of Mycobacteria, are several secretion systems responsible for the export of proteins to the cell envelope and the extracellular space. SecA2 is an ATPase that provides energy for the export of a subset of proteins. This dissertation confirms that SecA2 is required for the virulence of Mycobacteria and explores the role of SecA2 in the modulation of host immune responses in vivo. In a zebrafish and a mouse tail model of tuberculosis infection we have shown that the SecA2 of M. marinum is required for the maximal induction of several pro-inflammatory cytokines including TNF-alpha. Additionally, SecA2 has a role in granuloma formation and/or maintenance. In vitro studies of a DeltasecA2 deletion strain in M. marinum reveals that the mutant has an abnormal cell envelope by cryo-electron tomography, and increased sensitivity to SDS treatment. This work provides additional evidence supporting a role for SecA2 in modulating host immunity, and a novel role in cell wall morphology and function. |
