# Differential regulation of three DMSO reductases during enteric salmonellosis

> **NIH NIH F30** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $38,466

## Abstract

PROJECT SUMMARY
Non-typhoidal Salmonella are successful foodborne pathogens in part because of their ability to utilize diverse
nutrient sources to support disease in many hosts. Within the mammalian gut, catabolism of organosulfur
compounds by the host and/or the microbiota can lead to production of the electron acceptor dimethyl sulfoxide
(DMSO). The genome of Escherichia coli K12, a closely related gut-commensal bacterium, encodes a single co-
transcribed operon dedicated to the anaerobic reduction of DMSO (dmsABC) and has been used as a model
system to study DMSO respiration in Enterobacteriaceae. In contrast, Salmonella serotypes that cause enteric
disease encode three operons homologous to dmsABC, suggesting this pathway is important to support fitness
within the gut. Our prior work demonstrates that DMSO reduction is a biologically relevant pathway to support
Salmonella fitness during acute intestinal colonization. In vitro phenotyping suggests STM0964 is the dominant
homolog of dmsA, the catalytic subunit of a DMSO reductase, while STM4305 acts an alternate dmsA homolog
during anaerobic growth. However, there is a critical gap in our understanding of how the bacterium regulates
the use of each DMSO reductase and how each DMSO reductase contributes to fitness during enteric infection.
Genetic redundancy in anaerobic respiration pathways is a common theme in Enterobacteriaceae that allows
bacteria to benefit from changes in nutrient availability to regulate fitness in the gut. My preliminary data shows
that DMSO increases the promoter activity of the alternate dmsA homolog, STM4305. The promoter activity of
the dominant dmsA homolog, STM0964, is not activated by DMSO akin to E. coli dmsA, suggesting that
Salmonella possesses a novel mechanism for transcriptional regulation by DMSO. I hypothesize that
differential activation of DMSO reductases supports Salmonella fitness within the gut. In Aim I, I will
establish a mechanism for DMSO-mediated transcriptional regulation of the alternate DMSO reductase using
biochemical, genetic and RNA sequencing approaches. In Aim II, I will utilize fluorescence microscopy and
competitive infections to elucidate the contribution of each DMSO reductase during enteric infection of the bovine
host. The proposed work will integrate my veterinary training with large animal modeling of enteric disease and
advanced gene expression analysis to establish how Salmonella benefits from apparent genetic redundancy in
DMSO reduction. At the completion of fellowship training, I will be poised for success in a career as an
independent clinician-scientist with expertise in genetic approaches and animal modeling to study infectious
diseases of One Health significance.

## Key facts

- **NIH application ID:** 10897765
- **Project number:** 5F30AI169967-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Eddy Cruz
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,466
- **Award type:** 5
- **Project period:** 2023-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897765

## Citation

> US National Institutes of Health, RePORTER application 10897765, Differential regulation of three DMSO reductases during enteric salmonellosis (5F30AI169967-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10897765. Licensed CC0.

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