Shah, SwatiTuberculosis (Tb) is second only to HIV/AIDS as the most fatal disease caused by a single infectious agent. <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) is the causative agent of the disease and is an intracellular pathogen that first infects phagocytes in the lungs. To successfully establish an infection in the host and setup a replicative niche, the bacteria has to be able to evade detection and manipulate innate immune responses in an effort to delay induction of inflammation and the subsequent onset of adaptive immunity. The investigations in this dissertation are focused on three different innate immune evasion mechanisms employed by mycobacteria: (1) inhibition of inflammasome activation (2) secretion of virulence factors and (3) inhibition of apoptosis. First we demonstrated that unlike the avirulent mycobacterial species, <italic>Mtb</italic> limits the secretion of IL-1&#946; by inhibiting AIM2 inflammasome activation. Experiments revealed that <italic>Mtb</italic> was able to inhibit AIM2 activation and IFN-&#946; production induced by <italic>M. smegmatis</italic>/dsDNA (AIM2 ligand) in an ESX-1 dependent manner. <italic>Mtb</italic> did not affect the expression of AIM2 or IL-1&#946; but rather, inhibited the activation of the inflammasome itself as evidenced by a decrease in caspase-1 cleavage. In another study, we characterized one of the three gene regions (<italic>Rv1037c-Rv1040c</italic>) duplicated from the ESX-5 secretion system for its role in protein secretion, its effects on host cell immune responses and its virulence in a zebrafish model. We named this four gene region as ESX-5a. Even though the ESX-5a region is required for the secretion of Alanine-L dehydrogenase (ALD), it does not contain genes encoding for the components of a secretion system. Instead, a western blot analysis of the cell supernatants of an ESX-5 system mutant showed that ALD was exported via the parent ESX-5 secretion system. The <italic>Mtb</italic> ESX-5a mutant was found to be defective in inducing inflammasome activation and the <italic>M. marinum</italic> mutant was attenuated in the fish model. The final study focuses on screening for anti-apoptotic genes. <italic>In vitro</italic> infections with <italic>Mtb</italic> transposon mutants helped identify <italic>Rv1048c</italic> as a novel anti-apoptotic gene. As a result, we have identified several novel mechanisms by which <italic>Mtb</italic> achieves a survival advantage during initial infection.enDissertationMicrobiologyImmunologyCellular biology