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Deciphering Early Stages of Polyomavirus CNS Pathogenesis and Immunity

Award Number: R35NS127217
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Deciphering Early Stages of Polyomavirus CNS Pathogenesis and Immunity - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $896,585 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/1/2025	NON-COMPETING CONTINUATION	$896,585
														Subtotal = $896,585

Issue Date FY: 2024 ( Subtotal = $924,941 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	5/10/2024	SUPPLEMENT FOR EXPANSION	$70,699
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/6/2024	NON-COMPETING CONTINUATION	$869,688
2024	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/18/2023	NON-COMPETING CONTINUATION	$0
2024	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	5/23/2024	SUPPLEMENT FOR EXPANSION	-$15,446
														Subtotal = $924,941

Issue Date FY: 2023 ( Subtotal = $983,372 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/11/2023	NON-COMPETING CONTINUATION	$896,585
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/15/2023	SUPPLEMENT FOR EXPANSION	$86,787
														Subtotal = $983,372

Issue Date FY: 2022 ( Subtotal = $590,674 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/15/2022	NEW	$590,674
														Subtotal = $590,674

Grand Total All Awards = $3,395,572

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Deciphering Early Stages of Polyomavirus CNS Pathogenesis and Immunity

Award Number: R35NS127217

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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