# How Listeria senses and responds to different host environments

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $368,480

## Abstract

Project Summary/Abstract
Listeria monocytogenes is facultative intracellular food-borne pathogen that provides an extremely
amenable model for basic studies on host-pathogen interactions. This proposal is based on the results of a
genetic screen that revealed a critical role of bacterial redox sensing for the upregulation of virulence gene
expression in vivo. We found that L. monocytogenes glutathione synthase was upregulated during infection
and determined that glutathione is the allosteric activator of the major virulence transcription factor PrfA.
Based on these findings, and after decades of investigation by multiple groups, we successfully
recapitulated intracellular virulence gene expression by simply adding reducing agents to bacteria grown in
a chemically defined synthetic media. This finding led to another genetic screen to identify bacterial mutants
that were either more sensitive or resistant to the growth inhibitory property of high concentrations of
reducing agents. Analysis of the resistant mutants that arose from this screen led to the discovery that L.
monocytogenes possess a Flavin-based Extracellular Electron Transport chain (FLEET) that can transport
over 100,000 electrons/bacterium/second to flavin moieties present on two extracellular lipoproteins, PplA
and FrdA, which can transfer electrons to ferric iron and fumarate via activation of FrdA, which encodes a
fumarate reductase. We show that FLEET can mediated anaerobic growth using either ferric iron or
fumarate as electron acceptors. Mutants that were more sensitive to reducing agents clustered in perR, a
redox-sensing transcription factor that controls the transcriptional response to oxidative stress. We
hypothesize that the oxidative stress is being generated by FLEET that we show is producing superoxide in
the presence of oxygen. FLEET orthologues were found in 100s of Firmicute species including pathogens
and members of the microbiota and we propose that it represents a versatile electron transfer hub present
in diverse Gram-positive bacteria, that provides a selective advantage to bacteria growing anaerobically in
the intestine. We also propose that FLEET activity has other consequences aerobically that may have
profound effects on the cell biology of infection, virulence, and immunity.

## Key facts

- **NIH application ID:** 10165461
- **Project number:** 5R01AI027655-33
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** DANIEL A PORTNOY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,480
- **Award type:** 5
- **Project period:** 1988-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165461

## Citation

> US National Institutes of Health, RePORTER application 10165461, How Listeria senses and responds to different host environments (5R01AI027655-33). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165461. Licensed CC0.

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