# Mechanisms for Vibrio cholerae colonization and pathogenesis in zebrafish

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2021 · $386,000

## Abstract

PROJECT SUMMARY
The aquatic bacterium Vibrio cholerae causes human diarrheal disease that can range from mild to deadly.
Pandemic O1/O139 strains cause cholera, a potentially deadly disease, whereas non-O1/O139 strains, also
known as “environmental” V. cholerae, cause a range of diarrheal diseases from mild to severe. Animal models
have been useful in characterizing major V. cholerae virulence factors, but rabbits and mice are not natural V.
cholerae hosts and require absent or damaged microbiota to enable colonization. Vertebrate fish are natural V.
cholerae hosts and recent work has established zebrafish as a model that recapitulates the entire infectious
process in the presence of intact intestinal microbiota. Fish are rapidly colonized by V. cholerae exposure in
water, develop diarrhea, excrete large numbers of V. cholerae, and transmit the infection to naïve fish.
Because this is a model in a natural host, it presents new opportunities for V. cholerae study that are not
possible with mammalian models. However, the V. cholerae factors that act in fish pathogenesis are unknown
for both O1 and non-O1/O1319 strains. This proposal will examine the infectious processes used by both O1
and non-O1/O139 V. cholerae and test the following hypotheses: 1) V. cholerae produce specific colonization
factors in fish that are also important in human infections. These factors are shared among all V. cholerae
strains. This hypothesis will be tested using Tn-Seq to identify genes important for fish colonization. 2) V.
cholerae produces factor(s) that directly cause diarrhea. This hypothesis will be tested by knocking out known
toxins in each strain and measuring diarrhea. 3) V. cholerae perturbs specific components of the intestinal
microbiota, creating a niche for colonization. This hypothesis will be tested by assessing microbiome before
and after infection. 4) The type six secretion system (T6SS) is important for competition with intestinal
microbiota. This hypothesis will be tested by knocking out T6SS and further identifying T6SS effectors that are
important for this competition. 5) V. cholerae excreted by fish are hyperinfectious, as they are in human cholera
stool, and this is a likely source of V. cholerae outbreaks. This hypothesis will be tested by comparing
infectious doses required for colonization from in vitro grown and fish-passaged V. cholerae. 6) V. cholerae
shifts its gene expression program prior to host escape to enable transmission and contribute to
hyperinfectivity. This hypothesis will be tested using RNA-Seq to determine global changes in gene expression
between in vitro grown, actively colonizing, and excreted V. cholerae. Completion of the proposed work, using
zebrafish as a natural V. cholerae host model, will significantly advance our understanding of the
environmental lifestyle of V. cholerae in a natural reservoir, the requirements for V. cholerae to become a
pathogen, and should uncover new targets for therapeutics, environmental ...

## Key facts

- **NIH application ID:** 10129881
- **Project number:** 5R01AI127390-05
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** JEFFREY H WITHEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,000
- **Award type:** 5
- **Project period:** 2017-05-05 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129881

## Citation

> US National Institutes of Health, RePORTER application 10129881, Mechanisms for Vibrio cholerae colonization and pathogenesis in zebrafish (5R01AI127390-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10129881. Licensed CC0.

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