We are exploring pathogen-host interactions, particularly in the context of animal models relevant to human infection of clinically important enteric pathogens including Vibrio cholerae, Vibrio parahaemolyticus and enterohemorrhagic Escherichia coli (EHEC).

Major on-going projects include:

I. Use of infant rabbit models of diarrheal disease to study host-pathogen interactions. Studies of the biology of enteric pathogens during infection have been hampered by the lack of non-surgical small animal models of diarrheal disease. We found that infant rabbits orally inoculated with EHEC, V. cholerae or V. parahaemolyticus develop diarrheal diseases that mimic the respective human infections. We are taking advantage of these models to gain insights into bacterial physiology during growth in the host as well as host-pathogen interactions.

II. Development and implementation of new approaches to comprehensively identify pathogen and host factors critical for virulence using high throughput transposon- and CRISPR-based screens.

III. We developed an approach (STAMP) that utilizes high-throughput sequencing data to characterize pathogen population dynamics within an infected host. Such analyses reveal the extent and sites of host barriers to infection, as well as pathways by which pathogens disseminate within hosts. We are using STAMP to investigate V. cholerae transmission and to define the factors that control V. cholerae population dynamics. STAMP analyses are particularly interesting for pathogens that disseminate to secondary sites of infection through uncharacterized bottlenecks; e.g., we are using STAMP to investigate passage of Listeria monocytogenes from the GI tract to secondary infection sites. These studies will also identify pathogen and host factors that modulate dissemination routes and founding population sizes.

IV. D-amino acids in bacterial and host physiology. We found that diverse bacteria release a variety of D-amino acids both in culture and in the intestine. We are studying the mechanisms by which released D- amino acids control cell wall metabolism and cell shape as well as modulate host defense against pathogens and the composition of the intestinal microbiota.

V. Applying single molecule real time DNA sequencing to assess the extent, diversity and functional consequences of DNA modifications (e.g. methylation) in enteric pathogens.