# Regulation of Salmonella virulence by interspecies methylthioadenosine signaling

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $193,971

## Abstract

Abstract
Pathogenic bacteria within a mammalian host are bombarded by intercellular, interspecies, and cross-kingdom
signaling molecules and metabolites. For Salmonella enterica, multiple signals, including pH, bile, and short
chain fatty acids, regulate Salmonella Pathogenicity Island I (SPI-1) to trigger invasion and inflammation in the
gut. Recently, our lab demonstrated that the methionine-derived metabolite methylthioadenosine (MTA) is a
previously unrecognized signal produced by the host and pathogen that suppresses SPI-1, flagellar motility, and
in vivo virulence. These conclusions were drawn from experiments treating S. Typhimurium with MTA and by
characterizing a mutant with increased endogenous MTA. This mutant lacks the master repressor of the
methionine metabolism pathway, metJ. In addition to MTA’s effect on S. Typhimurium, MTA also modulates host
responses and is released into plasma during S. Typhimurium infection in mice and during sepsis in humans.
Thus, MTA can suppress S. Typhimurium virulence and its levels in the host undergo dramatic shifts during
infection. However, it is unknown if and how host- or microbiota-produced MTA signals to S. Typhimurium at the
crucial initial site of this host-pathogen conflict, the intestinal lumen. We hypothesize that MTA in the intestine is
dynamically regulated by host, commensal microbiota, and pathogen, and that shifts in MTA levels are sensed
by Salmonella to regulate virulence gene expression. Therefore, the first goal of this project is to characterize
contributions and consequences of host- and microbial-derived MTA during S. Typhimurium infection. MTA
levels in gut contents and tissue will be measured from germ-free and microbiome reconstituted mice at baseline
and with S. Typhimurium infection. Furthermore, we will manipulate host MTA levels through exogenous MTA
and the use of an inhibitor that specifically blocks host MTA metabolism. The second goal is to elucidate
mechanisms of MTA suppression of S. Typhimurium virulence. We will test whether MTA modulates regulators
of SPI-1 expression and if MTA facilitates broader gene expression changes through regulation of methylation.
Completion of these aims will identify whether MTA acts as an interspecies signal in the gut and identify how
MTA suppresses virulence. This work could improve clinical outcomes by demonstrating that existing methionine
metabolism inhibitors can suppress S. Typhimurium virulence.

## Key facts

- **NIH application ID:** 9849179
- **Project number:** 5R21AI144586-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Dennis Chun-Yone Ko
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,971
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849179

## Citation

> US National Institutes of Health, RePORTER application 9849179, Regulation of Salmonella virulence by interspecies methylthioadenosine signaling (5R21AI144586-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9849179. Licensed CC0.

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