# Innate Immune Mechanisms Controlling Flavivirus Neurovirulence

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $790,000

## Abstract

Summary
West Nile virus is a pathogen of global concern. Since its introduction to the US in 1999, it has caused thousands
of deaths and tens of thousands of hospitalizations. West Nile virus is transmitted to humans by the bite of
infected mosquitos; the virus mediates a febrile illness and can progress to invasive infection of the central
nervous system causing severe encephalopathy. WNV neuroinvasive disease also causes cognitive and motor
sequelae that can last for months or years after the virus is cleared. In order to successfully treat these
symptoms, gaining a clearer understanding of the immune response to WNV and the factors that determine the
initiation and severity of neuroinvasive disease is critical. There is incomplete understanding of what virus and
host determinants control or mediate WNV neuroinvasion, how the immune response to WNV within the CNS is
initiated and regulated, and how the acute response to WNV influences long-term inflammatory sequelae of
WNV encephalitis. The goal of the proposed studies is to address these knowledge gaps by gaining a molecular
understanding of WNV neuroinvasion, CNS immunity, and inflammatory sequelae. We will do this by deploying
newly-developed unique mouse models, recombinant forms of WNV, and an array of single-cell and spatial
transcriptomic and epigenomic methods. First, we will define the cells that initiate the immune response to WNV
in the periphery, and the targets of the cytokines produced by this response that control WNV neuroinvasion.
Second, we will define the signaling circuits by which WNV initiates and propagates inflammatory responses
within the CNS. Third and finally, we will use a recombinant WNV strain expressing Cre recombinase to mark
CNS cells that survive WNV infection and assess their contribution to persistent inflammatory sequelae that
persist after WNV clearance. New understanding gained from the proposed studies will significantly advance our
understanding of the determinants and consequences of WNV neuroinvasive disease, and will inform ongoing
efforts to mitigate and ameliorate these consequences in human patients.

## Key facts

- **NIH application ID:** 10912981
- **Project number:** 1R01AI183793-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Michael Gale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $790,000
- **Award type:** 1
- **Project period:** 2024-09-03 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912981

## Citation

> US National Institutes of Health, RePORTER application 10912981, Innate Immune Mechanisms Controlling Flavivirus Neurovirulence (1R01AI183793-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10912981. Licensed CC0.

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