# Global regulation in Clostridium difficile via phase variation of cyclic diguanylate signaling

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $508,480

## Abstract

PROJECT SUMMARY
Clostridium difficile is a major public health threat, causing disease ranging from mild diarrhea to potentially
fatal pseudomembranous colitis. C. difficile disease symptoms are largely mediated by the secreted cytotoxins,
TcdA and TcdB. Many aspects of the pathogenicity of this bacterium remains poorly understood, including how
C. difficile adapts to the host intestinal environment. The components of the bacterial cell surface play critical
roles in physiology and virulence and are commonly immunogenic antigens and potential antibiotic targets. In
C. difficile the signaling molecule cyclic diguanylate (c-di-GMP) controls the production of flagella, type IV pili,
and multiple additional cell surface proteins, indicating a key role for c-di-GMP in reorganizing the C. difficile
cell surface in response to the host intestinal environment. Phase variation is a means by which many bacterial
species introduce phenotypic heterogeneity into the population as a strategy to ensure survival of the
population in the face of changing selective pressures. We recently showed that flagella and toxins phase vary
in C. difficile, and sequencing analyses identified several other putative phase variable loci including two that
encode c-di-GMP hydrolases. Our central hypothesis is that C. difficile combines c-di-GMP signaling and
phase variation to coordinate global changes to the cell surface, enabling adaptation to extracellular pressures
encountered during colonization of the intestinal tract. The objective of this proposal is to define the
mechanisms of phase variation that control c-di-GMP signaling, the phenotypic responses to changes in c-di-
GMP, and the impact of these regulatory mechanisms on C. difficile physiology and virulence. To accomplish
this goal, we employ molecular genetics, biochemical techniques, and animal models of C. difficile disease to
examine phase variation and c-di-GMP signaling at the population and single cell levels. Our discovery that C.
difficile links phase variation with c-di-GMP signaling reveals a previously unknown mechanism for coordinated
modification of the bacterial cell surface. Completion of these aims may expose new targets for attenuating C.
difficile fitness in the host, facilitating efforts to combat this increasingly problematic pathogen.

## Key facts

- **NIH application ID:** 10020308
- **Project number:** 5R01AI143638-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** RITA TAMAYO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,480
- **Award type:** 5
- **Project period:** 2019-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020308

## Citation

> US National Institutes of Health, RePORTER application 10020308, Global regulation in Clostridium difficile via phase variation of cyclic diguanylate signaling (5R01AI143638-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020308. Licensed CC0.

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