# Role of Microglia in Protection Against West Nile Virus-induced CNS Injury: mechanisms and treatment strategies

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2024 · —

## Abstract

Treatments for virus-induced diseases of the central nervous system (CNS) are sub-optimal or
nonexistent. West Nile virus (WNV) is the most common cause of epidemic encephalitis within the US. This
proposal will investigate the role of microglia during WNV infections of the CNS and will evaluate microglial
stimulation as a potential treatment strategy for WNV-induced CNS disease.
 Virus infection of the CNS results in a robust host neuroinflammatory response, including the
activation of CNS immune cells (microglia). The role of microglia in virus-induced CNS disease remains
unclear. They likely play a protective role in facilitating the removal of infected cells and the recovery of
damaged neurons. However, many of the factors released by microglia may contribute to injury within the
CNS. Indeed, neuroinflammation in general and microglia activation in particular are key pathogenic
components following neurologic injury and during noninfectious forms of neurologic and neurodegenerative
disease. Our in vivo and ex vivo models will allow us to compare the role of microglia in the brain and spinal
cord. Since microglia are central to a variety of CNS injury and disease pathologies, including
neurodegenerative diseases, the proposed experiments will likely have wide reaching clinical implications.
 We have recently shown that depletion of microglia, with the colony stimulating factor receptor 1
(CSFR1) antagonist PLX5622, results in increased severity of WNV-induced CNS disease in mice that is
associated with an increase in CNS viral titers. In Specific Aim 1 of this proposal we will use PLX5622 targeted
depletion of microglia to determine whether microglia impact viral growth at the point of viral entry into the
CNS, viral replication within the CNS, or viral clearance. Microglia function to identify and remove invading
pathogens by phagocytosing infected or damaged cells, by acting as antigen presenting cells required to
generate a complete antigen specific T cell response, and by secreting immune modulatory molecules. In
Specific Aim 2 we will determine which of these mechanisms are required for microglia to inhibit WNV growth
in the CNS.
 In Specific Aim 3 we will determine the efficacy of microglial stimulation as a treatment strategy for
WNV-induced CNS disease. For these studies we will use granulocyte-macrophage colony-stimulating factor
(GM-CSF), a haematopoietic growth factor and proinflammatory cytokine, that induces, proliferates, and
activates microglia. Recombinant human GM-CSF is already FDA-approved to treat conditions in which white
blood cell counts are low, such as in certain types of leukemia or bone marrow transplant recipients. GM-CSF
and is currently being investigated as a potential treatment for cognitive problems related to Alzheimer's
disease. Mice will be treated with recombinant human GM-CSF (Leukine) and will be monitored to determine
viral CNS titers, virus-induced tissue injury and death, and the persistence of neurolo...

## Key facts

- **NIH application ID:** 10726593
- **Project number:** 5I01BX000963-11
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Kenneth L. Tyler
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726593

## Citation

> US National Institutes of Health, RePORTER application 10726593, Role of Microglia in Protection Against West Nile Virus-induced CNS Injury: mechanisms and treatment strategies (5I01BX000963-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10726593. Licensed CC0.

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