# Innate immune sensing of ER stress during bacterial infection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $429,056

## Abstract

ABSTRACT
Both pathogenic and non-pathogenic bacteria produce pathogen-associated molecular patterns (PAMPs) that
stimulate innate immune responses in their eukaryotic hosts via pattern-recognition receptors such as toll-like
receptors. Virulence factors of pathogens provide additional signals that allow the innate immune system to
differentiate between harmless commensals and pathogens. These signals include virulence factors, such as
Type III and Type IV secretion systems that translocate effector proteins into the host cell. Collectively, these
processes are detected by the immune system as “patterns of pathogenesis” and can activate cytosolic signaling
pathways. Brucella abortus is a stealthy pathogen expressing modified PAMPs that no longer serve as agonists
for pattern recognition receptors. As a result, host responses generated during B. abortus infection are entirely
dependent on detecting the function of its T4SS, as a pathogen-induced process. Here we propose to use this
organism to interrogate novel innate immune signaling pathways linking perturbation of endoplasmic reticulum
function to inflammation. The objectives of this application are to determine how activation of the IRE1α pathway
of the host cell’s unfolded protein response influences the outcome of infection with intracellular bacteria, by
eliciting inflammatory responses and providing inputs that drive survival or death of the infected cell. The
proposed research will test the hypothesis is that in macrophages, a NOD1/NOD2-containing signaling complex
detects perturbation of ER function during B. abortus infection to induce inflammatory responses and promote
survival of infected macrophages, while in a secretory cell type infection-induced ER stress triggers immunogenic
cell death, resulting in placentitis and abortion. Successful completion of this work will move the field forward by
determining how cells detects pathogen-induced perturbation of ER function and how the resulting response
drives cell survival vs cell death outcomes in different cell types. This concept has important ramifications not
only for bacterial pathogenesis, but also for understanding host-virus interactions, innate immunity and the
pathogenesis of inflammatory disorders associated with ER stress, such as type 1 diabetes, inflammatory bowel
disease and neuroinflammatory disease.

## Key facts

- **NIH application ID:** 9998656
- **Project number:** 2R01AI109799-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Renee M Tsolis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,056
- **Award type:** 2
- **Project period:** 2014-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998656

## Citation

> US National Institutes of Health, RePORTER application 9998656, Innate immune sensing of ER stress during bacterial infection (2R01AI109799-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9998656. Licensed CC0.

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