Project Details
Description
ABSTRACT
JC polyomavirus (JCPyV), a ubiquitous human pathogen, causes several devastating brain diseases in
immune compromised individuals. The most notable of these JCPyV-associated CNS diseases is the
frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML). PML, an
AIDS-defining lesion in the pre-cART epoch, has emerged as a life-threatening complication in patients
receiving immunomodulatory agents for autoimmune and inflammatory disorders and treatment for certain
hematological malignancies. Among the rapidly expanding list of PML-associated biologics, natalizumab
(Tysabri®) has the highest incidence and is an ominous sequela 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. No
anti-JCPyV agents are available. Polyomaviruses are species-specific. Lack of a tractable animal model of
polyomavirus-induced CNS disease is an acknowledged bottleneck to elucidating PML pathogenesis, the
immunological mechanisms that control JCPyV, in vivo evaluation of agents that inhibit polyomavirus
replication in tissue culture, and uncovering early events that presage irreversible JCPyV-associated
neuropathology. Using mouse polyomavirus (MuPyV), we developed a natural virus-host model of
polyomavirus-associated CNS disease. In this R35 application, we plan to leverage our three recent key
findings: (1) Mapping JCPyV-PML VP1 capsid protein mutations to MuPyV’s VP1 confers escape from virus-
neutralizing antibodies (nAb) while preserving CNS tropism; (2) IL-21 produced by high-affinity anti-MuPyV
CD4 T cells in the brain is required for formation and maintenance of MuPyV-specific brain resident-memory
CD8 T cells (bTRM); and (3) STAT1-dependent innate immunity limits infection of the ventricular ependyma, a
critical barrier to infection of the brain parenchyma. These findings lay the foundation for three key questions to
be addressed here: (1) Is the ependyma the staging ground for polyomavirus invasion of the brain
parenchyma?; (2) Does the integrity of the CD8 bTRM response to persistent infection depend on subset
heterogeneity?; and (3) Does T cell deficiency open the door for outgrowth of nAb-escape virus variants? The
proposed studies will make use of cutting edge advances in next-generation sequencing to uncover rare VP1
mutations in vivo, custom cryo EM image reconstruction approaches to define endogenous VP1 nAb epitopes
and nAb escape mechanisms, and high-resolution 3D imaging of intact mouse brains to visualize virus CNS
entry and spread. Findings from these studies will answer fundamental questions about innate and adaptive
immune control of polyomavirus CNS infection and conditions underlying dissemination of virus from the
periphery into the brain before development of irreversible neuropathology.
Status | Active |
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Effective start/end date | 5/1/22 → 4/30/25 |
Funding
- National Institute of Neurological Disorders and Stroke: $590,674.00
- National Institute of Neurological Disorders and Stroke: $896,585.00
- National Institute of Neurological Disorders and Stroke: $869,688.00
- National Institute of Neurological Disorders and Stroke: $70,699.00
- National Institute of Neurological Disorders and Stroke: $86,787.00
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