# Analysis of regulatory networks in Salmonella pathogenesis.

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $490,500

## Abstract

PROJECT SUMMARY:
 Nontyphoidal Salmonella infections are frequently associated with diarrhea in healthy people. Some
serovars such as Typhimurium are also common causes of bacteremia in HIV-infected people, and life-
threatening disseminated complications in immunocompromised individuals with defects in neutrophils,
macrophages or CD4 T cells. Sensor kinases and their cognate response regulators in two-component
systems orchestrate many virulence programs in Salmonella and many other pathogenic bacteria. In the
canonical activation of two-component systems, the sensor kinase is phosphorylated in response to cues
encountered during colonization and infection of the mammalian host. The transfer of the phosphoryl group
from the sensor kinase to the receiver domain of its cognate response regulator turns on virulence programs
essential for bacterial pathogenesis. We have made the unexpected discovery that two-component response
regulators are controlled by previously unknown allosteric interactions with thioredoxin. Our research has
shown that thioredoxin post-translationally controls several response regulators such as OmpR, PhoP and
SsrB, all of which govern key aspects of Salmonella pathogenesis. Strikingly, the post-translational control
exerted by thioredoxin on two-component signaling does not rely on the universally conserved thiol-disulfide
oxidoreductase enzymatic activity of this ancestral protein, but is contingent upon a hitherto uncharacterized
hydrophobic interfacial surface that has been preserved throughout the evolution of thioredoxin in bacteria,
archaea and eukaryotes. Our investigations indicate that most contributions of thioredoxin to Salmonella
pathogenesis are independent of its oxidoreductase activity but are carried out by this newly discovered
interfacial surface. The proposed research will test the hypothesis that thioredoxin leverages the binding
attributes of a conserved hydrophobic patch to establish protein-protein interactions with multiple response
regulators, thereby exerting broad post-translational control of two-component signaling. Specifically, we will
identify the interfacial residues that mediate oxidoreductase-independent functions of thioredoxin, and will
quantify the extent that the novel thioredoxin-binding face enables response regulators to activate Salmonella
virulence programs. Our research will elucidate previously unappreciated elements in the regulation of two-
component signaling, and will ascertain unprecedented, oxidoreductase-independent functions of thioredoxin.
The knowledge gained on the novel function of thioredoxin will not only shed light on key aspects of
Salmonella pathogenesis, but may ultimately broaden our understanding of a primordial function of
universally-expressed thioredoxin proteins. Our work will also provide far reaching insight into the regulation
of two-component systems, which represent a dominant signaling pathway in bacteria. Drugs that specifically
inhibit interactions...

## Key facts

- **NIH application ID:** 10262941
- **Project number:** 5R01AI155493-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Andres Vazquez-Torres
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $490,500
- **Award type:** 5
- **Project period:** 2020-09-11 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10262941

## Citation

> US National Institutes of Health, RePORTER application 10262941, Analysis of regulatory networks in Salmonella pathogenesis. (5R01AI155493-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10262941. Licensed CC0.

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