# Mechanisms and impacts of astrocyte inflammasome activation during viral encephalitis

> **NIH NIH F32** · WASHINGTON UNIVERSITY · 2022 · $67,582

## Abstract

PROJECT SUMMARY
 Viral infections of the central nervous system (CNS) pose a particularly difficult challenge to the host
immune system. Virus must be cleared from the CNS without significant immune-mediated damage to
neuronal tissues. In recent years, it has been increasingly recognized that survivors of viral encephalitides,
such as West Nile virus neuroinvasive disease (WNND), suffer from longterm neurocognitive sequelae. Past
research from our laboratory has modeled this phenomenon in mice by direct inoculation of attenuated West
Nile virus into the third ventricle of the brain. In this model, mice recover from encephalitis, but immune-
mediated damage causes adverse cognitive sequelae. Inflammatory astrocytes produce interleukin-1β after
viral infection and interferon-γ-producing T cells drive microglia activation. Each of these pathways negatively
impacts hippocampal synapse recovery, hippocampal neurogenesis, and visuospatial learning.
 Astrocytes are not directly infected by West Nile virus in vivo, but they nonetheless display NLRP3
inflammasome activation and downstream production of active caspase-1 and interleukin-1β. The signals that
drive activation of the NLRP3 inflammasome activation in astrocytes during viral infection remain completely
unknown. However, astrocytes express the P2 purinergic receptor P2RX7, which can mediate inflammasome
activation in macrophages exposed to high concentrations of extracellular ATP. Here, I propose that neuronal
synapse elimination during viral encephalitis releases supraphsyiologic levels of extracellular ATP, leading to
astrocyte inflammasome activation. In Aim 1, I will seek to confirm this hypothesis by generating a novel
mouse strain that specifically and inducibly lacks P2RX7 on astrocytes. In addition, I propose that heightened
extracellular ATP levels signal to neuronal stem cells via P2RX7, driving their differentiation towards reactive
astrogenesis rather than neurogenesis. I hypothesize that this pathway may contribute towards the lack of
hippocampal neurogenesis in our model of WNND. In Aim 2, I will investigate this possibility by infecting
animals with P2RX7-deficient neural stem cells with West Nile virus and monitoring for changes in
hippocampal neurogenesis and visuospatial learning ability. Together, these Aims will characterize novel
functions of the purinergic receptor P2RX7 during neuroinvasive viral infection, potentially identifying a target
for pharmacologic therapies that reduce the severity of post-infectious neurocognitive sequelae.

## Key facts

- **NIH application ID:** 10424785
- **Project number:** 1F32NS126238-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Veronica Anjali Dave
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424785

## Citation

> US National Institutes of Health, RePORTER application 10424785, Mechanisms and impacts of astrocyte inflammasome activation during viral encephalitis (1F32NS126238-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10424785. Licensed CC0.

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