Investigating the Role of Protease-mediated signaling in M. tuberculosis Virulence

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TITLE Investigating the Role of Protease-mediated signaling in M. tuberculosis Virulence ABSTRACT The bacterium M. tuberculosis (Mtb ) persists as a threat to human health, with tuberculosis (TB) killing an estimated 1-2 million people annually. Unfortunately, a molecular understanding of how Mtb evades the immune system is lacking. This critical gap in knowledge slows the design of new therapies that seek to improve TB vaccine efficacy or to promote sterilizing immunity in TB patients. My hypothesis is that when Mtb infects a host macrophage, it deploys proteases to degrade proteins involved in the immune response. I propose to explore the hypothesis that secreted Mtb proteases contribute to virulence by cleaving host proteins. We will use a unique combination of proteomics methods to 1) identify potential targets of secreted Mtb proteases, and to 2) globally profile proteolysis events during Mtb infection. I will then use genetic analysis in both M. tuberculosis and the host to disrupt both the bacterial proteases and their putative host substrates to evaluate the role that proteolysis plays in TB pathogenesis.