# Integrated Stress Response-mediated macrophage innate immunity during maladapted Salmonella enterica infection

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $42,094

## Abstract

ABSTRACT
Infection induced host cell stress underlies many host-pathogen engagements, yet the mechanisms by which
host cell stress influences the innate immune response to infection remain poorly understood. The Integrated
Stress Response (ISR) is an evolutionally conserved intracellular signaling pathway allowing cells to adapt to
environmental and pathological conditions. Upon activation of one or more of the four stress sensing kinases,
the signaling cascade converges into one central pathway and the ISR quickly controls cellular programming
through transcriptional and translational regulation to stimulate cellular repair, metabolic reprogramming, and
cell to cell signaling in an effort to return to homeostasis. My preliminary data demonstrate that the human
adapted pathogen, Salmonella enterica serovar Typhi (STY), activates the murine macrophage ISR during
infection. As the causative agent of typhoid fever, STY is a global health burden with millions of cases per year
and tens to hundreds of thousands of deaths annually. By using a maladapted host model of infection, this
research aims to understand STY-restricting host factors typically evaded in human macrophages, allowing for
future targeted drug development against this global pathogen. Further preliminary findings demonstrate that
induction of the ISR by STY requires the ISR kinase GCN2, a sensor of nutrient stress and ribosomal dysfunction.
I find that BMDMs lacking GCN2 produce lower levels of inflammatory cytokines and permit higher STY burden
during infection than WT controls. Additional preliminary data suggest that GCN2 controls macrophage
polarization and metabolic reprogramming in response to STY. Together, these data inform my hypothesis that
S. Typhi activation of the macrophage ISR shapes the innate immune response and infection outcomes. To test
this hypothesis, I will perform two aims that reveal the role of GCN2 in shaping macrophage metabolism and the
macrophage functions impacted by ISR activation in response to STY. Using cell culture, metabolomics, and in
vivo infection techniques, this proposal will capture how cellular stress defines the potential of a critical innate
immune cell during STY infection. Discoveries made through completion of these aims will be significant as
studies of S. Typhi infection biology have limited due to STY’s human-restricted host adaptation.

## Key facts

- **NIH application ID:** 10994355
- **Project number:** 1F31AI186289-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Zachary Michael Powers
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,094
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994355

## Citation

> US National Institutes of Health, RePORTER application 10994355, Integrated Stress Response-mediated macrophage innate immunity during maladapted Salmonella enterica infection (1F31AI186289-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10994355. Licensed CC0.

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