# The role of Salmonella protease PgtE in evading host immune responses

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $73,772

## Abstract

Project Summary
 Bacterial infections remain a leading cause of morbidity and mortality worldwide and a critical health issue
due to increasing antibiotic resistance and limited vaccines. Non-typhoidal Salmonella (NTS) serovars such as
Salmonella enterica serovar Typhimurium (STm) are a leading cause of inflammatory diarrhea in otherwise
healthy individuals, causing infections that are usually localized to the gut. Among immunocompromised
individuals, children, and elderly, STm can cause a potentially lethal bacteremia that requires antibiotic treatment.
Pivotal to innate host defense in preventing the spread of bacteria from the gastrointestinal tract to the
bloodstream are antimicrobial peptides, complement system proteins, and phagocytic cells including
macrophages and neutrophils. Pathogenic strains of STm can subvert the phagolysosome to survive
intracellularly in macrophages, whereupon the autophagy system emerges as a critical step for killing intracellular
STm. PgtE, a STm outer membrane protease, has been previously described to cleave over a dozen mammalian
protein substrates in vitro, including complement protein C3, but these activities have only been observed with
avirulent mutant strains possessing a defective outer membrane. In recent years, a newly emergent clade of
invasive STm has been responsible for an epidemic of bacteremia in sub-Saharan Africa, with several studies
suggesting an increased expression of PgtE as an important virulence mechanism although the mechanism
remains unknown. Our preliminary studies suggest that PgtE plays an important role during infection in both the
initial mucosal colonization and in the systemic phase with a virulent STm. Our central hypothesis is that after
STm has been phagocytosed, STm utilizes PgtE to protect the disrupted outer membrane from antimicrobial
peptides, complement, and autophagy killing, thereby promoting its survival in the host. In Aim 1, I will determine
the role of PgtE in enabling STm to evade IL-22-mediated gut epithelial defenses after STm is phagocytosed in
the lumen. In Aim 2, I will determine how PgtE subverts complement component C3 signaling and macrophage
autophagic killing. This work will provide a framework on how pathogens utilize proteases to evade the immune
system with potential novel therapeutic targets.

## Key facts

- **NIH application ID:** 10694847
- **Project number:** 5F32AI169989-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Michael Hweemoon Lee
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $73,772
- **Award type:** 5
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694847

## Citation

> US National Institutes of Health, RePORTER application 10694847, The role of Salmonella protease PgtE in evading host immune responses (5F32AI169989-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10694847. Licensed CC0.

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