# Astrocyte innate immune mechanisms of post-viral cognitive dysfunction

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $393,750

## Abstract

ABSTRACT
This proposal is focused on the pivotal role of astrocytes in molecular mechanisms
underlying neurocognitive sequelae of flavivirus encephalitis. WNV is the leading cause
of domestically acquired arboviral disease in the United States. In addition to the acute
neuroinvasive syndromes and persistent motor deficits, patients that recover from WN
neuroinvasive disease (WNND) experience significant long-term cognitive sequelae,
including high rates of memory impairment and abnormalities in executive function. We
recently established a novel murine model of recovery from intracranial infection with a
mutant WNV (WNV-NS5-E218A), which leads to ongoing microglia activation with
synapse elimination, decreased adult neurogenesis, and spatial learning defects that
persist months after viral clearance These effects on synapses were also observed in
patients who succumbed to WNND. While these data provide some molecular
explanations for poor spatial learning in WNV-recovered subjects, the mechanisms
underlying lack of recovery of the hippocampal circuit are unclear. We recently
demonstrated that WNND is associated with T cell-derived interferon(IFN)γ, and
microglial-derived complement promote elimination of hippocampal CA3 presynaptic
terminals, with lack of recovery due to the generation of interleukin(IL)-1β-expressing
activated astrocytes. Indeed, inactivation of IL-1R1 signaling in WNV-recovered animals
promotes adult neurogenesis, synaptic repair, and prevents defects in spatial learning.
These reactive astrocytes also express recently identified markers of neurotoxicity
(H2.D1, Gbp2, psmb8), suggesting viral-induced effects on cognition might be
perpetuated by the generation of astrocytes with a redirected cell fate. Indeed, increased
expression of some of these genes (GFAP, Gpb2, psmb8) is observed in human cortical
astrocytes treated with IFNβ, also highly expressed within the WNV-infected CNS. Prior
research has suggested multiple cellular origins of reactive astrocytes with activated
microglia being a potential key player in directing astrogliosis18,19. Similarly, the activation
of the inflammasome complex within myeloid cells has been implicated in IL-1β
production with IL-1 targeting multiple cell types including neural precursor cells20,21. We
hypothesize that macrophage-derived IL-1 directs neuronal precursor cells toward
an astrocyte fate during viral encephalitis. We further hypothesize that during
recovery, activated microglia promote the differentiation of astrocytes towards
neurotoxic phenotypes that inhibit hippocampal repair and recovery from
neurocognitive deficits via effects of innate immune cytokines on neural
precursor cells (NPC).
Aim 1: Define the cellular targets of astrocyte-derived, anti-neurogenic cytokines
in neurocognitive dysfunction during recovery from flavivirus encephalitis.
Aim 2: Define innate immune mechanisms that direct and maintain astrogliosis
during WNV infection and recovery.
Aim 3: Define astrocyte-sp...

## Key facts

- **NIH application ID:** 10115451
- **Project number:** 1R01NS116788-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Robyn S. Klein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,750
- **Award type:** 1
- **Project period:** 2020-12-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115451

## Citation

> US National Institutes of Health, RePORTER application 10115451, Astrocyte innate immune mechanisms of post-viral cognitive dysfunction (1R01NS116788-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10115451. Licensed CC0.

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