# The Role of Type VI Secretion in Cholera Pathogenesis

> **NIH NIH R01** · CITY COLLEGE OF NEW YORK · 2021 · $591,349

## Abstract

PROJECT SUMMARY/ABSTRACT
There is a gap in our understanding of how specific lineages of Vibrio cholerae cause outbreaks of cholera - an
infection of the small intestine that triggers severe watery diarrhea, dehydration, and, too often, death. Cholera
is endemic in many regions of the world, causing over 120,000 deaths every year. Cholera is also one of the first
diseases to emerge when the health care system and sanitation infrastructure break down during an economic
or civil crisis, as witnessed just recently in Yemen with 500,000 cases and 2,000 deaths.
The scientific premise for this proposal is a longstanding appreciation that cholera outbreaks emerge from single
clonal lineages – strains that are closely related genetically. Although its natural aquatic environment harbors a
diverse V. cholerae population, with both toxigenic (producing the main virulence factors of cholera toxin and
toxin-coregulated pilus) and non-toxigenic strains, cholera outbreaks are caused by single clonal lineages.
We propose that toxigenic strains use the type VI secretion system (T6SS) as an active competition mechanism
to prevent other strains from colonizing the small intestine. The T6SS structurally resembles the injection
apparatus of T4 bacteriophage and delivers toxic T6SS effectors into adjacent bacteria. Delivery of effectors is
lethal unless the receiving cell produces immunity proteins that sequester the incoming toxins.
The T6SS is encoded in three distinct loci on the chromosome. Each locus hosts a horizontally acquired genetic
element with a distinct toxin–immunity pair called a module. Together, the three effector modules in a strain
comprise its effector module set (e.g., AAA-module set for toxigenic strains). We discovered that strains with
identical modules are compatible and co-exist, while strains with different modules compete on contact.
Our central hypothesis is that toxigenic V. cholerae acquired the most competitive T6SS module set (AAA) to
exclude incompatible cheater strains. To test our hypothesis, we will resolve how the AAA module set is acquired
(Aim I), how it is used in vivo (Aim II) and how it contributes to clonal dominance (Aim III).
This proposal investigates how bacterial competition mechanisms contribute to the clonal nature of outbreaks,
allowing us to exploit strategies that interfere with the ability of toxigenic lineages to expand and cause cholera.

## Key facts

- **NIH application ID:** 10274892
- **Project number:** 7R01AI139103-03
- **Recipient organization:** CITY COLLEGE OF NEW YORK
- **Principal Investigator:** Stefan Pukatzki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $591,349
- **Award type:** 7
- **Project period:** 2019-01-18 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274892

## Citation

> US National Institutes of Health, RePORTER application 10274892, The Role of Type VI Secretion in Cholera Pathogenesis (7R01AI139103-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10274892. Licensed CC0.

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