# The Role of the RIP Kinases in Coordinating Neuroinflammation and Host Defense

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $441,250

## Abstract

Necroptosis is a form of programmed cell death that is executed by activation of the Receptor Interacting
Protein Kinases (RIPKs), RIPK1 and RIPK3. While this cell death pathway has been the subject of intense
study, physiological settings in which it is important have remained elusive. We have found that mice lacking
RIPK3 are highly susceptible to infection by the neuroinvasive flavivirus West Nile virus (WNV). RIPK3
knockout animals are unable to control viral growth within the central nervous system (CNS), because they
display a profound defect in the recruitment of immune cells into this tissue. Notably, RIPK3-deficient mice
also fail to control Zika virus (ZIKV) infection, and display neurological impairments and ascending paralysis
upon infection with this pathogen. Surprisingly, the protective role of RIPK3 in this setting is wholly
independent of its role in inducing programmed cell death; rather, RIPK3 is required for normal production of
inflammatory chemokines and immune cell trafficking in the WNV-infected CNS. Given these unexpected
preliminary data, the central hypothesis of this application is that virus-induced RIPK3 activation within the
CNS does not trigger cell death, but rather activates an inflammatory transcription program is required
for neuroinflammation, immune cell recruitment, and host protection. This application will investigate this
hypothesis by focusing on three Aims. First, we will work to understand how RIPK3 is engaged within the CNS
to promote host protection, using conditional deletion and transgenic expression of RIPK3 within this tissue in
combination with cutting-edge imaging approaches. Next, we will use biochemical methods and novel mouse
models to understand the downstream targets of RIPK3 that are responsible for the coordination of
neuroinflammation. Finally, we will investigate the role of RIPK3 in host protection against ZIKV infection, and
investigate the unexpected defects in motor function observed in ZIKV-infected RIPK3 knockout mice.
Together, this work will define a novel signaling pathway responsible for host defense against neuroinvasive
viral pathogens that represent a significant threat to global health.

## Key facts

- **NIH application ID:** 9846191
- **Project number:** 5R01AI132595-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Andrew Atwell Oberst
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,250
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846191

## Citation

> US National Institutes of Health, RePORTER application 9846191, The Role of the RIP Kinases in Coordinating Neuroinflammation and Host Defense (5R01AI132595-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9846191. Licensed CC0.

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