# Global regulators converge to orchestrate metabolism, biofilm, and pathogenesis

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $591,679

## Abstract

Project Summary
Diarrheal disease is a leading cause of morbidity and mortality in resource-poor areas. In order to colonize the
intestine and cause disease, successful bacterial pathogens must sense and respond to intestinal signals by
altering both metabolism and virulence factor expression. We hypothesize that by understanding the critical
intestinal signals and the bacterial regulatory networks they activate, we can devise simple dietary alterations
that prevent or mitigate morbidity and mortality.
We focus on Vibrio cholerae, the agent of the severe diarrheal disease cholera. Because the metabolic
pathways we study are highly conserved, these findings also serve as a paradigm for other bacteria that cause
diarrhea. The goal of this work is to elucidate the complex and highly conserved regulatory network that is
activated when V. cholerae enters the intestinal environment.
In the first 4-year funding period of this grant, we explored the role of a global regulator of metabolism and
virulence known as glucose-specific Enzyme llA. We showed that this regulator is membrane-associated
through an N-terminal amphipathic helix and that membrane association is critical for its interaction with
integral membrane protein partners that it regulates. Based on this work, we hypothesize that the inner
membrane of the bacterial cell may act as a platform for regulatory proteins that sense and respond to
nutritional signals in the intestinal environment.
During the previous funding period, we discovered that the subcellular location of the global transcription
factor, the cAMP receptor protein (CRP), is regulated in response to environmental conditions. In the current
funding period, we propose to follow up on these observations by investigating regulation of CRP subcellular
localization, the mechanism by which subcellular localization alters CRP activation of gene transcription, and
the functional significance of CRP subcellular localization for V. cholerae virulence. We hypothesize that if the
subcellular localization of CRP can be controlled via host diet, it may be possible to reduce pathogen virulence
and thereby the morbidity and mortality caused by cholera.

## Key facts

- **NIH application ID:** 10380787
- **Project number:** 5R01AI112652-06
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** PAULA I WATNICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $591,679
- **Award type:** 5
- **Project period:** 2014-08-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380787

## Citation

> US National Institutes of Health, RePORTER application 10380787, Global regulators converge to orchestrate metabolism, biofilm, and pathogenesis (5R01AI112652-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380787. Licensed CC0.

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