UC Berkeley

No organism on earth is exempt from the threat of pathogenic invasion. Although bacteria are commonly perceived as potential assailants, bacteria themselves endure the constant threat of predation by bacteriophage (phage, viruses of bacteria). While mechanisms of bacterial immunity were initially assumed to be simple and limited by the energetic cost of maintenance, recent expansions in the depth of DNA sequencing have illuminated a vast and complex landscape of genes, mobile genetic elements, and even resident prophage (phage that integrate into the host chromosome) involved in bacterial defense against phage infection. Beyond specific genetically encoded anti-phage mechanisms, recent evidence has emerged detailing bacterial physiological responses to environmental signals that confer phage resistance. This suggests that the protective capacity of the bacterial immune system is not determined by a small number of genes, but instead by an organized ensemble of defense genes responding to infections by specific phage and general host responses that confer broader resistance through physiological changes. In this work, we investigated the role of transcriptional regulatory changes in phage defense for multiple facets of the bacterial immune system of Vibrio cholerae. V. cholerae is a bacterial pathogen that frequently encounters phage predation and accordingly possesses an impressive repertoire of phage defense strategies. First, we explored the transcriptional regulatory interplay between a complex mobile element and the phage it defends against. The mobile element is a phage satellite that restricts infection by a specific phage and often utilizes phage-derived components to facilitate its own replication and dissemination. We identified a mechanism of targeted phage transcriptional modulation by the satellite that allows the element to balance phage inhibition with self-propagation. Second, we investigated the impact of intestine-relevant stimuli on V. cholerae-phage interactions, which frequently occur in the context of cholera infection in the human gut. We identified a combination of signals that stimulate surface modification in V. cholerae. The surface modification reduces availability of an outer membrane moiety that is often essential for initiating phage infection. This represents a novel innate immune strategy in V. cholerae that acts independently of systems that respond specifically to phage infection. Broadly, this work examines the crucial role of precise transcriptional regulation in the remarkable the V. cholerae immune system, deconvoluting complex interactions between mobile genetic elements and phages, and detailing interactions between bacterial host and the environment that impact bacterial susceptibility to phage infection.