# ROLE OF CARBON METABOLISM AND VIRULENCE OF SHIGELLA FLEXNERI

> **NIH NIH R37** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $396,250

## Abstract

Shigella species are invasive human pathogens that cause bacillary dysentery, or shigellosis, a
potentially fatal diarrheal disease. The global burden of shigellosis is estimated at more than 200 million
cases per year. There is currently no effective vaccine against Shigella, and drug resistance is
widespread and on the rise; thus, there is a critical need to identify novel Shigella targets for
immunization and new antibiotics. One promising approach is to target metabolic processes that are
important for pathogenesis, but not for survival of Shigella in the host environment. Inhibiting such
pathways would be less likely to select for resistant Shigella or to disrupt the normal gut microbiota.
Our work has shown that Shigella flexneri uses mixed acid fermentation to break down glycolysis
intermediates during growth within host cells. This process is critical for S. flexneri pathogenesis, but is
not required for growth of the bacteria, either inside or outside host cells. Mixed acid fermentation
leads to the production of formate, which is excreted by S. flexneri into the host cell cytosol. Formate
induces expression of S. flexneri virulence genes that are required for cell-to-cell spread. Our hypothesis
is that, as the bacteria multiply, formate levels reach a threshold that can be sensed by S. flexneri as a
signal to begin the process of spreading to neighboring cells, thus linking cell density with the need to
move deeper into the intestinal epithelium to find new resources. The goal of this study is to
investigate how formate is sensed by the bacteria, and how this signal leads to changes in gene
expression that promote cell-to-cell spread and evasion of host immunity. We propose to identify key
players in the formate sensing pathway in order to derive a model for how the formate signal is relayed
from the cell surface to its target genes. We will also determine the downstream effects of formate
signaling on both S. flexneri and host cell gene expression. Historically, Shigella studies have been
hampered by the lack of a physiologically relevant host-pathogen model system. We have recently
demonstrated that critical aspects of Shigella pathogenesis are faithfully reproduced in human intestinal
enteroids (HIEs), ‘mini-intestines’ derived from human intestinal biopsies. We propose to use HIEs to
determine both the Shigella and host cell transcriptomes in response to formate. This will allow
investigation of gene expression and metabolism during the course of a Shigella infection in fully
differentiated, non-transformed, native human tissue. We have assembled the necessary strains and
reagents, and we have the expertise to carry out these experiments, which we predict will lead to vital
new information in the search for novel shigellosis treatment and prevention strategies.

## Key facts

- **NIH application ID:** 10162477
- **Project number:** 5R37AI016935-35
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Shelley M. Payne
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 1980-09-30 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162477

## Citation

> US National Institutes of Health, RePORTER application 10162477, ROLE OF CARBON METABOLISM AND VIRULENCE OF SHIGELLA FLEXNERI (5R37AI016935-35). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10162477. Licensed CC0.

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