Quorum-sensing mediated communication between pandemic Vibrio cholerae and phage VP882

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PROJECT SUMMARY/ABSTRACT Bacteria are bombarded by infecting viruses, called phages, in natural habitats. Upon infection of a host, phages must undertake one of two lifestyles: lysogeny where the phage remains in the host and is passed down to offspring, or lysis where the phage replicates, kills the host, and spreads to new cells. Phages have been thought to transition from lysogeny to lysis exclusively in response to host stress and DNA damage. New research from the Bassler laboratory has revealed that phages can monitor host communication molecules, called autoinducers. In a process called quorum sensing, bacteria produce, release, and detect autoinducers, and in response, orchestrate group behaviors. Quorum-sensing-responsive phages detect host-produced autoinducers and exploit the information they garner to drive their lysis-lysogeny lifestyle transitions. These recent findings position me to discover how phages manipulate bacterial hosts and the consequences to the host, to the multi- species bacterial community of which the host is a member, and to the eukaryotic host in which all the entities reside. The overarching goal of my research is to define how cross-domain communication between vibriophage VP882, the first phage discovered to “eavesdrop” on quorum sensing, and its host, the global pathogen Vibrio cholerae, launches the phage lytic cycle. Using a combination of genetic, biochemical, and structural approaches, I will identify the molecular mechanisms underlying this host-phage chemical communication process. First, I will learn skills in bacterial genetics from experts in the Bassler laboratory and conduct a genetic screen to identify the repressor of the quorum-sensing-induced phage lytic cycle. Second, I will use biochemical methods to quantitatively characterize interactions between two key signaling components in the quorum- sensing-induced phage lysis pathway. Lastly, I will rely on my background in structural biology to solve the structures of these same signaling components, individually and in complex, enabling atomic-level-resolution understanding of the interactions required for the phage to undergo lifestyle transitions. The ideal outcomes of my research are a mechanistic understanding of inter-domain chemical communication and new possibilities for development of phage therapies. Honing my skills in bacterial genetics, protein biochemistry, and macromolecular crystallography over the course of my postdoctoral training will enable me to launch an independent research program at a top-tier research institution.