Abstract Mycobacterium tuberculosis (Mtb) causes pulmonary tuberculosis (TB) in humans. In 2017 alone, ~10.0 million new cases were reported, leading to approximately ~1.3 million deaths. There are no effective vaccines for TB and only sub-optimal chemotherapeutics exist. IL-1 is a cytokine that increases host resistance against Mtb infections. Mtb is able to limit the amount of IL-1 production by inhibiting the host cell inflammasome activation. There is a gap in our understanding of how Mtb exploits host cell signaling in order to inhibit the activation of the inflammasome. We describe for the first time that Mtb can inhibit the activation of the NLRP3 inflammasome and we identified the first Mtb gene (PknF) important for this inhibition. We performed a gain-of-function genetic screen and identified 5 other genomic regions of Mtb mediating the inhibition of the AIM2 inflammasome. We think that the discovery of specific Mtb genes involved in inhibiting the host inflammasome activation (Specific Aim 1) will allow for the characterization of the molecular mechanisms of inhibition (Specific Aim 2) and for testing their importance for virulence of Mtb (Specific Aim 3) during the course of the research proposal. We believe that our findings will have great translational potential since a greater understanding of the molecular mechanisms of host cell inflammasome activation will provide novel targets for development of adjunctive Mtb drugs and of host-directed therapeutics.