# Listeria monocytogenes physiology and host pathogen interactions

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $491,061

## Abstract

ABSTRACT
Listeria monocytogenes is a gram-positive, opportunistic, intracellular bacterial pathogen that causes food borne
illness. Given its well-characterized infection cycle and genetic amenability, L. monocytogenes provides a
powerful tool to interrogate the fundamental aspects of intracellular bacterial pathogenesis and the host immune
response to invasion by intracellular pathogens. L. monocytogenes that enter into the host cell cytosol secrete
the second messenger signaling nucleotide, c-di-AMP, resulting in innate immune activation by the host cell. We
recently identified the host protein RECON as a key mediator of this response. RECON is an enzyme whose
activity is inhibited by c-di-AMP. C-di-AMP inhibition of RECON results in the accumulation of the ROS byproduct
4-hydroxy-2-nonenal (4-HNE), which augments NF-kB activation, resulting in elevated nitric oxide synthase
expression and NO production during infection. Intriguingly, we have revealed that NO produced by the host cell
promotes L. monocytogenes intracellular motility, rather than restricting bacterial growth, and that L.
monocytogenes exhibits extreme NO resistance. Additionally, preliminary studies have revealed that 4-HNE is
ubiquitously induced by eukaryotic cells following exposure to bacteria and that this reactive aldehyde exhibits
antimicrobial effects on bacteria analogous to NO. Furthermore, L. monocytogenes exhibits extreme resistance
to the antimicrobial effects of 4-HNE and induces a specific transcriptional response to 4-HNE exposure, which
we hypothesize promotes survival within the infected host. We have begun in vitro biochemical studies, in vivo
forward genetic studies, and the murine models of infection to interrogate the mechanisms by which L.
monocytogenes counteracts the antimicrobial effects of NO and 4-HNE and utilizes NO to promote virulence. In
Aim I, we will interrogate the mechanisms used by L. monocytogenes to detoxify and counteract the antimicrobial
effects of 4-HNE. In Aim II, we propose to detail the molecular mechanisms of NO resistance and the impacts
on bacterial virulence. Finally, in Aim III we will detail the mechanism of NO induced L. monocytogenes actin-
based motility and explore the in vivo impacts of this process on bacterial invasion and dissemination. Together
these studies will define the molecular mechanisms of exquisite antimicrobial innate immune responses
employed by L. monocytogenes to promote survival within the eukaryotic host.
.

## Key facts

- **NIH application ID:** 9971206
- **Project number:** 2R01AI116669-06
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Joshua Woodward
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $491,061
- **Award type:** 2
- **Project period:** 2015-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971206

## Citation

> US National Institutes of Health, RePORTER application 9971206, Listeria monocytogenes physiology and host pathogen interactions (2R01AI116669-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971206. Licensed CC0.

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