# Role of microglia in MHV-induced demyelination

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $326,881

## Abstract

C57BL/6 mice infected with the neurotropic rJ2.2 variant of the JHM strain of mouse hepatitis virus
(rJ2.2) develop acute and chronic demyelinating encephalomyelitis and thereby serve as a useful
model for the human disease multiple sclerosis. The overall objective of this project has been to
understand virus-host interactions, to enhance virus clearance and minimize tissue damage. In the past
funding period, we concentrated on aspects of the T cell response that were pathogenic but protective
and others that were regulatory, dampening CD4 T cell-mediated immunopathological changes.
However, before a T cell response can clear virus, the host must mount a well-orchestrated and robust
innate immune response. Our recent work has focused on two aspects of this early innate response,
both involving microglia, which are the resident myeloid cells in the CNS. First, we showed that
microglia are critical for protection. Although microglia have important roles in immune surveillance and
maintenance of homeostasis in the CNS, their role in the context of infection remains ill-defined. Our
results show that they are key for protection from rJ2.2 infection. Second, we found that signaling of a
single eicosanoid, prostaglandin D2 (PGD2), through its DP1 receptor, found on myeloid cells including
microglia, was required for optimal survival in rJ2.2-infected mice. In the absence of DP1 signaling, type
1 IFN (IFN-I) expression was delayed and IL-1β expression was increased, suggesting that PGD2/DP1
signaling was critical for a balanced immune response. The absence of PGD2/DP1 signaling resulting in
dysregulated microglia function. Therefore, the central objective of this project is to better
understand the many roles that microglia have in enhancing the host response to viral
infections in the brain and thereby improving outcomes in the context of viral encephalitis (and
ultimately, demyelinating disease). This objection will be addressed in the following specific aims.
Specific Aim 1: To determine the basis for lethal outcomes in microglia-depleted rJ2.2-infected mice. In
this aim, mice will be treated with PLX6522, which depletes microglia. We will monitor virus clearance
and immune function after treatment. We will assess whether macrophage numbers, function or gene
expression is changed in the absence of microglia. Specific Aim 2: To determine the role of PGD2/DP1
signaling in microglia in rJ2.2-infected mice. In this aim, we will assess effects of PGD2/DP1 on viral
control and the host immune response. We found that a PYRIN domain only protein, PYDC3, was
downregulated in microglia of mice lacking DP1 signaling. PYDC3 has similarities to IFN-I-inducible
human proteins that regulate inflammasome formation and activation but homologous proteins have not
been identified in mice. One of the goals of this aim is to understand the interactions and roles of
prostaglandin D2 signaling, IFN-I expression and inflammasome function.

## Key facts

- **NIH application ID:** 9850637
- **Project number:** 5R01NS036592-22
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Stanley Perlman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,881
- **Award type:** 5
- **Project period:** 1997-09-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850637

## Citation

> US National Institutes of Health, RePORTER application 9850637, Role of microglia in MHV-induced demyelination (5R01NS036592-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850637. Licensed CC0.

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