Characterizing the Effects of Immune Activity on Intestinal Epithelial Regeneration During a Vibrio cholerae Infection.

The aquatic pathogen Vibrio cholerae is responsible for the severe, and potentially deadly disease, cholera, that claims roughly 100,000 lives each year. Vibrio passes through the host stomach, and enters the intestine where it encounters a dense community of gut-resident bacteria that form a natural barrier to infection. To dismantle the bacterial barrier, Vibrio injects toxic molecules into susceptible prey. By eliminating competitor bacteria Vibrio has access to host cells, where Vibrio grows, and causes the severe, rice-water diarrhea that hallmarks cholera disease. Despite the importance of bacterial competition for infection, we know very little about the effects of interbacterial warfare on the host. Researchers in my group use zebrafish and fruit flies as animal models to address this important question. Flies and fish are ideal for this work, as they develop diarrheal disease upon Vibrio infection, and have similar gut architecture to mammals. Importantly, we have access to a large number of tools for genetic experiments with fish and flies. Thus, studying disease in the fly and fish models has considerable potential to help us understand how Vibrio causes disease in humans. Recently, we showed that Vibrio-dependent killing of gut bacteria activates evolutionarily conserved immune responses in the fly host. Remarkably, immune activation is not protective for the host. Instead, immune activation blocks the repair of intestinal cells damaged by Vibrio, greatly enhancing disease severity. In this project, we will use our expertise in genetics and live models of Vibrio infection to understand how an immune response is detrimental to host recovery from infection. We believe this work represents a significant step towards identifying actionable therapies for a global health and economic burden.