# A Mouse Model to Define Immunovirologic Determinants of Polyomavirus CNS Disease

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $386,301

## Abstract

ABSTRACT
Progressive Multifocal Leukoencephalopathy (PML) is a life-threatening demyelinating brain disease in
immune-compromised individuals caused by the JC polyomavirus (JCPyV), a ubiquitous human pathogen. No
anti-JCPyV agents are available. Among the expanding compendium of PML-associated biologics,
natalizumab has the highest incidence (1-2%) and is an ominous complication for multiple sclerosis (MS)
patients who otherwise benefit from dramatic reductions in relapses using this immunomodulatory agent. Drug
withdrawal, the only therapeutic option for PML, is often complicated by a high-mortality cerebral inflammatory
reaction. Moreover, three non-PML JCPyV-CNS diseases have recently been described. Lack of a tractable
animal model of polyomavirus-induced CNS disease is a well-recognized bottleneck to elucidating PML
pathogenesis and the immunological mechanisms that control JCPyV (both essential for identifying PML risk
factors), and in vivo evaluation of antiviral agents that inhibit polyomavirus replication in tissue culture. Using
mouse polyomavirus (MuPyV), we developed a natural virus-host model of polyomavirus-associated
demyelination. In work supported by the parent R01, we found a sizeable MuPyV-specific, brain resident-
memory CD8 T cell (bTRM) population. TRM are disseminated throughout the body as non-recirculating cells,
where they provide frontline defense against reinfection. Our understanding of TRM biology comes largely from
analysis of these cells in mucosal barriers; far less is understood about TRM in nonmucosal sites of infection,
particularly those with large numbers of nonrenewable cells (e.g., CNS). We discovered a critical connection
between CD4 T cells and differentiation of functional MuPyV-specific CD8 bTRM. Our preliminary data provide
strong scientific premise for our central hypothesis that IL-21 is the “help” proffered by CD4 T cells for
generating MuPyV-specific CD8 bTRM. CD4 T cell insufficiency and IL-21 signaling-deficiency each resulted in
loss of antiviral CD8 T cells expressing a TRM phenotype and inability to survive in the brain without resupply
from the circulation. Gene expression pathway analyses of CD4 T cell-unhelped antiviral CD8 T cells during
persistent MuPyV encephalitis revealed dysregulation of IL-21 and Notch signaling pathways, and their
potential convergence via STAT3. MuPyV-specific CD8 bTRM express functional Notch receptors, whose
activation is diminished in the absence of CD4 T cell help. Notch receptors have recently been reported to
support establishment of tissue-resident memory CD8 T cells. For Specific Aim 1, we hypothesize that IL-21
is a major component of the help provided by CD4 T cells to guide differentiation of brain-infiltrating CD8 T
cells into TRM. For Specific Aim 2, we hypothesize that IL-21 and Notch signaling cooperate via STAT3
activation to generate CD8 bTRM. If these hypotheses prove correct, they will provide essential insights into
the mechanisms involved in ma...

## Key facts

- **NIH application ID:** 9920216
- **Project number:** 5R01NS088367-07
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Aron Eliot Lukacher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,301
- **Award type:** 5
- **Project period:** 2014-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920216

## Citation

> US National Institutes of Health, RePORTER application 9920216, A Mouse Model to Define Immunovirologic Determinants of Polyomavirus CNS Disease (5R01NS088367-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920216. Licensed CC0.

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