# Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $525,005

## Abstract

Project Summary
Immune defense against bacterial infection requires signaling pathways that activate expression of
inflammatory mediators to control and clear infection. Many pathogens inhibit these signaling pathways in
order to evade host immune defenses. In particular, Yersinia injects a virulence factor, YopJ, which potently
blocks key aspects of NF-ΚB and MAPK signaling pathways. How immune defense is mediated against
pathogens that block immune signaling pathways remains poorly understood. NF-κB blockade in macrophages
exposed to bacterial PAMPs leads to cell death. Importantly, our recently published data demonstrate that
RIPK1 kinase activity is required for Yersinia-induced cell death, and that RIPK1 kinase activity is critical for
resistance to Yersinia infection and innate inflammatory cytokine production in vivo. This suggests that RIPK1-
induced death triggered by Yersinia is a key immune protective mechanism. Our new studies indicate that IKK
phosphorylates RIPK1 to limit induction of cell death by inflammatory stimuli, suggesting that Yersinia blockade
of IKK releases RIPK1 from this inhibitory effect. How RIPK1 kinase activity and cell death promote host
defense against bacterial infection is not known. Our central hypothesis is that RIPK1-mediated cell death
triggered in response to pathogen-mediated NF-κB and MAPK blockade releases pro-inflammatory signals,
such as IL-1 cytokines and intracellular alarmins that enable uninfected bystander cells to produce key
inflammatory mediators such as TNF, which control infection by pathogens that interfere with innate signaling.
This is an important problem as this pathway likely responds to many pathogens that block critical innate
immune signaling pathways and in the context of pathological stimuli that lead to RIPK1-induced cell death.
We propose three Specific Aims to address this important gap in our knowledge. First we will define the
molecular basis for how RIPK1 kinase activation occurs in response to YopJ blockade of IKK signaling, and
test the role of this pathway in anti-bacterial immune defense. Second, we will define immune responses of
infected and bystander cells, and will define the contribution of RIPK1-dependent cell death pathways to anti-
bacterial host defense in vivo. Finally, we will determine the contribution of TNF signaling by bystander cells to
antibacterial immune defense and will define the cell-type specific requirement for RIPK1- and TNFR-
dependent cell death in host immune defense against Yersinia.

## Key facts

- **NIH application ID:** 9857556
- **Project number:** 5R01AI139102-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** IGOR E BRODSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,005
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857556

## Citation

> US National Institutes of Health, RePORTER application 9857556, Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense (5R01AI139102-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857556. Licensed CC0.

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