# Innate immune mechanisms of virologic control and recovery from flavivirus encephalitis

> **NIH NIH R56** · WASHINGTON UNIVERSITY · 2020 · $775,277

## Abstract

ABSTRACT
Viral infections within the brain pose a unique challenge for the immune system: the host must trigger an effective
immune response to control and clear the infection while minimizing neuronal damage. The immunological
mechanisms that balance these responses during neurotropic virus infection are not well understood. West Nile
virus (WNV) is an emerging neurotropic flavivirus that causes annual epidemics of mosquito-borne encephalitis
on a global scale. Following delivery into the skin, WNV replicates in the lymph nodes and spleen followed by
entry into the CNS. Here, WNV infects and replicates within neurons, where it is detected by the cytoplasmic
RNA helicases RIG-I and MDA5 which, via activation of the mitochondrial antiviral signaling protein (MAVS),
lead to the expression of antiviral and proinflammatory proteins, including T cell chemoattractants. The absence
of CD8+ T cells leads to uncontrolled virus replication, significant neuronal injury within the brain and loss of
protection. To understand how the brain impacts T cell responses during WNV infection, we performed
transcriptional profiling on antigen-specific CD8+ T cells isolated from the spleen and brain at early and late
times post-WNV infection. We observed that antigen-specific CD8+ T cells infiltrate the CNS around day 7 post-
infection (pi), were polyfunctional (IFN-γ, TNF-α) and persist in the brain through day 90 pi. Subpopulations of
persistent CD8+ T cells were observed to develop markers consistent with resident memory T cells and maintain
persistently elevated levels of type II IFN (IFN-γ). We recently found that CD8+ T cell-derived IFN-γ signaling
to microglia, in conjunction with the expression of complement, drives the elimination of presynaptic termini
within the hippocampus, which underlies spatial learning defects during recovery from WNV. Further, IFN-γ
signaling also promotes astrocyte expression of interleukin (IL)-1, which limits synaptic repair. These findings
strongly suggest that the brain microenvironment impacts CD8+ T cell programming that is important for
mediating viral control during the acute phase of infection. However, these same antigen-specific CD8+ T cells,
through the actions of IFN-γ, contribute to cognitive deficits during the recovery phase. Based on these
observations, we hypothesize that during the acute phase of WNV infection, MAVS signaling within neurons and
are important for coordinating CD8+ T cell-mediated viral control, neural synapse formation and neurogenesis.
However, during the recovery phase, we believe that MAVS signaling within neurons and microglia promote
persistence of brain- resident antigen-specific CD8+ T cells that contribute to defects in spatial learning. To
address these hypotheses, we seek to determine: 1) the cell-specific contribution of MAVS signaling within the
brain during acute WNV infection; and 2) the impact of CD8+ T cell persistence on CNS homeostasis after
recovery from viral encephalitis. This st...

## Key facts

- **NIH application ID:** 10247164
- **Project number:** 1R56AI147623-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Robyn S. Klein
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $775,277
- **Award type:** 1
- **Project period:** 2020-09-14 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247164

## Citation

> US National Institutes of Health, RePORTER application 10247164, Innate immune mechanisms of virologic control and recovery from flavivirus encephalitis (1R56AI147623-01A1). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10247164. Licensed CC0.

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