# Encephalitic viral infection and susceptibility to dopaminergic neurotoxins

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2021 · $603,534

## Abstract

Project Summary
The overall focus of this Virtual Consortium project is on neuroinflammation and the neuro-immune axis as a
critical link between viral infection and susceptibility to injury from environmental neurotoxins. Neuroinflammatory
activation of glial cells may represent an important causal link in the `two-hit' theory of neurological disease,
sensitizing susceptible brain regions to damage from distinct environmental stressors and thereby promoting the
onset of clinical disease. The proposed Virtual Consortium will examine how infection with commonly
encountered RNA viruses, including Western Equine Encephalitis virus (WEEV) and H1N1 influenza virus, the
current worldwide pandemic flu virus, influences the severity of neurological outcomes following exposure to
neurotoxic metals and pesticides. Neuroinflammatory mechanisms examined in animal models will be compared
to advanced PET imaging of neuroinflammation in individuals occupationally exposed to manganese (Mn) in
conjunction with an analysis of their history of viral exposure. This Virtual Consortium will examine signaling
mechanisms in microglia and astrocytes that regulate neuroinflammatory injury following exposure to viruses
and selected environmental neurotoxins using both transgenic mouse models as well as clinical imaging in Mn-
exposed patients. The Consortium will bring together collaborators in neurovirology and neurodegeneration
(Richard Smeyne, Thomas Jefferson University), neurology and clinical imaging (Brad Racette, Washington
University, St. Louis) and neuroinflammation (Ronald Tjalkens, Colorado State University) to identify key
neuroinflammatory mechanisms modulating the response to infectious and neurotoxic environmental exposures
that could increase the risk of developing neurodegenerative disease. It is our central hypothesis that
encephalitic viral infection causes a persistent inflammatory phenotype in microglia and astrocytes that enhances
susceptibility to neurotoxic injury. This hypothesis will be tested by the following interconnected Specific Aims:
Specific Aim 1 (Tjalkens, Colorado State University) - Identify inflammatory signaling pathways in microglia
modulated by Western Equine Encephalitis Virus (WEEV) that promote glial activation and neuronal injury from
manganese and rotenone; Specific Aim 2 (Smeyne, Thomas Jefferson University) - Determine mechanisms by
which H1N1 influenza virus alters the effects of manganese and rotenone on neuronal injury; Specific Aim 3
(Racette, Washington University School of Medicine) - Characterize patterns of neurological dysfunction and
microglial activation in manganese (Mn) exposed workers. We expect that this Virtual Consortium will have a
significant impact on our understanding of interactions between environmental neurotoxins and viruses that can
promote neurological disease, which are currently only poorly understood. Such interactions are likely to have
enormous implications to public health, given the widespre...

## Key facts

- **NIH application ID:** 10240481
- **Project number:** 5R01ES030937-03
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** RONALD TJALKENS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $603,534
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240481

## Citation

> US National Institutes of Health, RePORTER application 10240481, Encephalitic viral infection and susceptibility to dopaminergic neurotoxins (5R01ES030937-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10240481. Licensed CC0.

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