The human polyomaviruses, JCV and BKV, establish lifelong persistent infection in kidney but are generally not associated with disease in healthy individuals. In immunosuppressed patients reactivation and spread of JCV to the central nervous system causes a fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). Reactivation of BKV in immunosuppressed renal transplant patients causes polyomavirus associated nephropathy (PVN) that leads to graft dysfunction and loss. Viral DMA and viral gene products from both JCV and BKV have been detected in human cancers but a causal link has not been established. Our long-term goals are to define the role of virus receptors in cellular invasion, spread, and pathogenesis. During the last funding cycle we discovered that the JCV receptor is a complex consisting of alpha(2,6) linked sialic acid and the 5HT2a receptor. Both components are critical for infection as cells missing either component are not susceptible to infection by JCV. Our efforts are now focused on identifying the critical determinants that allow JCV to productively interact with this receptor complex. As the 5HT2a receptor is a G protein coupled receptor and JCV binding to cells induces a signal that is essential for infection we will determine whether JCV signals directly through this receptor. During the last funding cycle we discovered that the receptor for BKV is an N-linked glycoprotein containing alpha(2,3)-linked sialic acid, that signaling is important for BKV infection, and that BKV does not share receptor specificity with JCV. A detailed molecular genetics approach is proposed to identify the critical residues in the BKV capsid protein VP1 that interacts with sialic acid containing receptors. We will also compare JCV and BKV induced signaling and entry pathways in the cell.
Our specific aims are to 1. define the interactions between human polyomavirus capsid proteins and host cell receptors, 2. define the molecular pathways that link virus- induced signaling at the plasma membrane to transcriptional responses in the nucleus, and 3. map the infectious entry pathway leading to the nucleus and identify the viral and cellular proteins involved at each step. Data resulting from these studies will yield novel insights into the pathogenesis of human polyomavirus induced disease and may lead to novel therapies to prevent or treat these diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071878-13
Application #
7810623
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Blair, Donald G
Project Start
1997-09-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
13
Fiscal Year
2010
Total Cost
$256,956
Indirect Cost
Name
Brown University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Haley, Sheila A; Atwood, Walter J (2014) An animal model for progressive multifocal leukoencephalopathy. J Clin Invest 124:5103-6
Zins, Stephen R; Nelson, Christian D S; Maginnis, Melissa S et al. (2014) The human alpha defensin HD5 neutralizes JC polyomavirus infection by reducing endoplasmic reticulum traffic and stabilizing the viral capsid. J Virol 88:948-60
Assetta, Benedetta; Maginnis, Melissa S; Gracia Ahufinger, Irene et al. (2013) 5-HT2 receptors facilitate JC polyomavirus entry. J Virol 87:13490-8
Gee, Gretchen V; O'Hara, Bethany A; Derdowski, Aaron et al. (2013) Pseudovirus mimics cell entry and trafficking of the human polyomavirus JCPyV. Virus Res 178:281-6
Lipovsky, Alex; Popa, Andreea; Pimienta, Genaro et al. (2013) Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus. Proc Natl Acad Sci U S A 110:7452-7
Neu, Ursula; Allen, Stacy-Ann A; Blaum, Bärbel S et al. (2013) A structure-guided mutation in the major capsid protein retargets BK polyomavirus. PLoS Pathog 9:e1003688
Nelson, Christian D S; Carney, Dan W; Derdowski, Aaron et al. (2013) A retrograde trafficking inhibitor of ricin and Shiga-like toxins inhibits infection of cells by human and monkey polyomaviruses. MBio 4:e00729-13
Ferenczy, Michael W; Marshall, Leslie J; Nelson, Christian D S et al. (2012) Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 25:471-506
Nelson, Christian D S; Derdowski, Aaron; Maginnis, Melissa S et al. (2012) The VP1 subunit of JC polyomavirus recapitulates early events in viral trafficking and is a novel tool to study polyomavirus entry. Virology 428:30-40
Maginnis, Melissa S; Haley, Sheila A; Gee, Gretchen V et al. (2010) Role of N-linked glycosylation of the 5-HT2A receptor in JC virus infection. J Virol 84:9677-84

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