# Salmonella pathogenicity island 2 triggers pore-induced intracellular trap formation to evade killing by neutrophils

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $235,500

## Abstract

PROJECT SUMMARY
 Salmonella serovars can cause severe extraintestinal disease in humans. While
neutrophils can kill extracellular bacteria using NADPH oxidase-dependent killing
mechanisms, macrophages support growth of the pathogen in tissue. The main virulence
factor promoting bacterial survival at extraintestinal sites, a type III secretion system
(T3SS-2) encoded by Salmonella pathogenicity island (SPI)-2, functions in evading
NADPH oxidase-dependent killing by host phagocytes. Paradoxically, T3SS-2-deficient
mutants can grow within macrophages in the liver and spleen of mice, suggesting that the
virulence factor does not evade NADPH oxidase-dependent killing by macrophages in
vivo. Our central hypothesis is that entrapment of S. Typhimurium within the cellular
debris of a dead macrophage (termed the pore-induced intracellular trap or PIT) protects
the pathogen from neutrophil NADPH oxidase-dependent killing mechanisms during
efferocytosis of cellular debris containing viable bacteria. Through this mechanism, T3SS-
2-dependent macrophage PIT formation enables S. Typhimurium to evade NADPH
oxidase-dependent killing by neutrophils when the pathogen exits from infected cells to
form new infection foci. We will test key aspects of our hypothesis by determining whether
localization in macrophage PITs protects Salmonella from neutrophil ROS (Specific Aim
1) and by elucidating how Salmonella T3SS-2 enables complement to reach intracellular
bacteria in PITs (Specific Aim 2). Successful completion of the proposed experiments will
establish the novel concept that macrophage PIT formation is a virulence strategy of
intracellular pathogens to evade neutrophil-mediated host defenses.

## Key facts

- **NIH application ID:** 9975575
- **Project number:** 1R21AI143929-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Hirotaka Hiyoshi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $235,500
- **Award type:** 1
- **Project period:** 2020-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975575

## Citation

> US National Institutes of Health, RePORTER application 9975575, Salmonella pathogenicity island 2 triggers pore-induced intracellular trap formation to evade killing by neutrophils (1R21AI143929-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975575. Licensed CC0.

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