# Control of virulence in Vibrio cholerae by fatty acids

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2020 · $405,000

## Abstract

Vibrio cholerae O1 causes the fatal epidemic disease cholera. The ability of V. cholerae to cause
disease in humans is dependent upon two primary virulence factors, the toxin-coregulated pilus (TCP), a
critical colonization factor, and cholera toxin (CT). The expression of these factors is controlled by a highly
regulated transcriptional cascade that serves as a paradigm for the regulation of bacterial virulence.
Expression of the cascade is initiated at the tcpPH promoter by a cooperative interaction between the
regulators AphA and AphB. TcpPH and ToxRS are homologous pairs of transmembrane regulators that then
cooperate to activate expression from the toxT promoter. ToxT, an AraC-type regulator, directly activates the
expression of TCP and CT. Transcriptional activation of the virulence cascade is strongly dependent upon a
variety of stimuli from the external environment. The long-term goals of this proposal are to understand the
molecular basis of virulence gene regulation in V. cholerae so as to facilitate the development of new
strategies to control its infectivity. Through a collaborative effort involving laboratories with expertise in
structural biology, virulence gene regulation and pathogenesis, we have found that exogenous unsaturated
fatty acids (UFAs), which are components of human bile, are capable of binding to ToxT and impairing its
ability to activate virulence gene expression. UFAs bind into a ligand pocket in the N-terminal domain of ToxT
and inhibit its dimerization as well as its ability to bind to DNA. Bicarbonate, which neutralizes the acid that
comes from the stomach, has been shown to function as a second in vivo signal that, in contrast to UFAs,
stimulates ToxT and enhances its DNA binding through an unknown mechanism. We have recently identified a
new link between fatty acids (FAs) and virulence gene expression in the current pandemic strain of V. cholerae
with the discovery that the master regulator of FA metabolism, FadR, influences the translation of ToxT by an
unknown mechanism. This proposal will build upon the ToxT structural and functional data, as well as our
recent studies involving FadR, in order to elucidate several key mechanisms involved in regulating the
expression of the virulence cascade. In Aim 1, we propose to elucidate the allosteric mechanisms controlling
the dimerization of ToxT and to investigate the opposing effects of UFAs and bicarbonate on this process. In
Aim 2, we propose to elucidate the mechanism by which FadR influences the translation of ToxT in V.
cholerae. These studies will contribute significantly toward our understanding of how virulence gene
expression is regulated in V. cholerae and will likely provide new avenues for antivirulence drug discovery.

## Key facts

- **NIH application ID:** 9970380
- **Project number:** 5R01AI120068-05
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Fredrick Jon Kull
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970380

## Citation

> US National Institutes of Health, RePORTER application 9970380, Control of virulence in Vibrio cholerae by fatty acids (5R01AI120068-05). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/9970380. Licensed CC0.

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