# Identifying the formate-sensory mechanism in Shigella flexneri

> **NIH NIH R03** · WESTERN MICHIGAN UNIVERSITY · 2022 · $75,500

## Abstract

Abstract
The enteric bacteria and intracellular human pathogen Shigella causes hundreds of millions of cases of the
diarrheal disease shigellosis (dysentery) per year worldwide and as many as one million deaths. Currently,
there is no approved vaccine for the prevention of shigellosis, and the incidence of antimicrobial resistance
amongst Shigella spp. is on the rise. To cause disease, Shigella flexneri is ingested into a human host, and
then migrates through the digestive tract and invades colonic epithelial cells where it replicates and causes
acute inflammation; this pathogenesis requires a coordinated program of virulence gene expression for S.
flexneri to adapt to different host environments and states. Even within a host epithelial cell, S. flexneri
virulence gene expression is dynamic, and one signal that S. flexneri uses to regulate this expression is its own
production of formate. As S. flexneri replicates within a host cell, it produces and secretes formate, a byproduct
of mixed acid fermentation, and this formate accumulates in the host cell. S. flexneri then senses this formate
accumulation to positively regulate the expression of virulence genes associated with intercellular spread and
dampening the host immune response; however, the mechanism by which S. flexneri recognizes formate
accumulation within a host cell is unknown. The goal of this study is to identify the S. flexneri system used to
sense extracellular formate accumulation in the host cell cytoplasm during pathogenesis. The first aim of this
proposal is to use the differential radial capillary action of ligand assay (DRaCALA) to identify S. flexneri
formate binding proteins, and then characterize their role in promoting S. flexneri plaque formation. The second
aim of this proposal is to perform a genetic screen of a S. flexneri transposon mutant library to identify genes
associated with the S. flexneri response to formate. Identifying this important virulence regulatory system will
enable future studies to characterize the dynamics of formate signaling in infected host cells, and potentially
provide novel targets for antimicrobial therapeutics and vaccine development.

## Key facts

- **NIH application ID:** 10428655
- **Project number:** 5R03AI156432-02
- **Recipient organization:** WESTERN MICHIGAN UNIVERSITY
- **Principal Investigator:** Benjamin J. Koestler
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $75,500
- **Award type:** 5
- **Project period:** 2021-06-14 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428655

## Citation

> US National Institutes of Health, RePORTER application 10428655, Identifying the formate-sensory mechanism in Shigella flexneri (5R03AI156432-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428655. Licensed CC0.

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