Cholera is a severe diarrheal disease that affects millions of people each year, and primarily affects persons living in low-resource countries. Host factors that contribute to Vibrio cholerae susceptibility are only partially understood, and the mechanism through which natural infection generates long-term protective immunity is not known. New approaches to the study of host-pathogen interactions are needed to understand susceptibility to infection, bacterial shedding among infected persons, and the development of protective immunity. Human gut microbes have an increasingly recognized role in enteric infections, including in the expression of virulence factors and persistent shedding of pathogens in stool. The candidate seeks a K08 Mentored Clinical Scientist Research Career Development Award to acquire formal training and mentorship to study the influence of human gut microbes upon three aspects of V. cholerae infection. First, the investigator aims to understand how the human gut microbiome influences susceptibility to infection, and to then explore mechanisms of gut microbe-V. cholerae interactions in vitro. Second, the candidate seeks to understand how gut microbes influence the duration of V. cholerae shedding among infected persons. Third, by studying the gut microbes in duodenal biopsies from cholera patients during acute illness, the investigator will learn how gut microbes at the site of V. cholerae colonization influence the subsequent development of immune responses to V. cholerae. During the course of this award, the candidate will explore the host microbiome-pathogen interaction at the mucosal surface using V. cholerae, a model noninvasive enteric pathogen. The candidate is clinically trained in Infectious Diseases with a background in epidemiology and immunology, and seeks advanced formal training in analysis of genomic datasets and microbial population structure to apply new technologies to the study of the gut microbiota and enteric infections. By implementing the studies described in this proposal with the guidance of expert mentors, the candidate will be poised for a career as an independent investigator studying the gut microbiome-enteric pathogen interactions at the mucosal interface.

Public Health Relevance

Vibrio cholerae is a bacterium that causes cholera, a severe diarrhea that can be fatal if untreated. Bacteria that naturally live in the human gut may explain why some people exposed to V. cholerae develop cholera and others do not. This proposal seeks to understand if and how human gut bacteria influence V. cholerae infection and the development of immune responses to V. cholerae.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Hall, Robert H
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Massachusetts General Hospital
United States
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Midani, Firas S; Weil, Ana A; Chowdhury, Fahima et al. (2018) Human Gut Microbiota Predicts Susceptibility to Vibrio cholerae Infection. J Infect Dis 218:645-653
Bourque, Daniel L; Bhuiyan, Taufiqur Rahman; Genereux, Diane P et al. (2018) Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways. Infect Immun 86:
Levade, Inès; Terrat, Yves; Leducq, Jean-Baptiste et al. (2017) Vibrio cholerae genomic diversity within and between patients. Microb Genom 3: