The long-term objectives of this application are to understand the mechanisms of cell entry by the mouse polyoma virus. This virus has a broad host range. It replicates and induces tumors in a wide variety of cell types in its natural host.
The Specific Aims are first to determine whether certain glycolipids constitute the only class of cell receptors for the virus or whether certain glycoproteins may also serve as functional receptors. This will be done using a mouse deficient in glycolipid biosynthesis but unaffected in glycoprotein pathways. Investigations will be carried out to identify the steps in virus disassembly in the endoplasmic reticulum and the cellular factors the virus utilizes to undergo the necessary steps of disassembly and to enter the nucleus. Factors under investigation in this regard are the oxidoreductase ERp29, protein disulfide isomerase, the derlin chaperones, and Ran GTPase. A specific goal is to generate in vitro and characterize the altered particle that is primed for membrane insertion and escape from the ER. Finally, in collaboration with Dr. Xiaowei Zhuang's lab at Harvard, attempts will be made to follow single virus particles in live cells as they enter and establish infection. We will attempt to produce polyoma particles labeled both on the minichromosome and the outer capsid protein with fluorescent probes to study decapsidation and separation of these components. The processes of cell entry by many viruses are not fully understood. The polyoma group includes several viruses that are pathogenic in humans, including JC, BK and possibly SV40. Understanding the pathways of cell entry by these viruses may suggest opportunities for anti-viral therapy or prevention. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082395-08
Application #
7472373
Study Section
Virology - A Study Section (VIRA)
Program Officer
Blair, Donald G
Project Start
1999-11-30
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
8
Fiscal Year
2008
Total Cost
$449,660
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
You, John; O'Hara, Samantha D; Velupillai, Palanivel et al. (2015) Ganglioside and Non-ganglioside Mediated Host Responses to the Mouse Polyomavirus. PLoS Pathog 11:e1005175
Chinnapen, Daniel J-F; Hsieh, Wan-Ting; te Welscher, Yvonne M et al. (2012) Lipid sorting by ceramide structure from plasma membrane to ER for the cholera toxin receptor ganglioside GM1. Dev Cell 23:573-86
Carroll, John; Dey, Dilip; Kreisman, Lori et al. (2007) Receptor-binding and oncogenic properties of polyoma viruses isolated from feral mice. PLoS Pathog 3:e179
Gilbert, Joanna; Ou, Wu; Silver, Jonathan et al. (2006) Downregulation of protein disulfide isomerase inhibits infection by the mouse polyomavirus. J Virol 80:10868-70
Lilley, Brendan N; Gilbert, Joanna M; Ploegh, Hidde L et al. (2006) Murine polyomavirus requires the endoplasmic reticulum protein Derlin-2 to initiate infection. J Virol 80:8739-44
Magnuson, Brian; Rainey, Emily K; Benjamin, Thomas et al. (2005) ERp29 triggers a conformational change in polyomavirus to stimulate membrane binding. Mol Cell 20:289-300
Gilbert, Joanna; Dahl, Jean; Riney, Cathy et al. (2005) Ganglioside GD1a restores infectibility to mouse cells lacking functional receptors for polyomavirus. J Virol 79:615-8
Fink, Aliza K; Gurwitz, Jerry; Rakowski, William et al. (2004) Patient beliefs and tamoxifen discontinuance in older women with estrogen receptor--positive breast cancer. J Clin Oncol 22:3309-15
Gilbert, Joanna; Benjamin, Thomas (2004) Uptake pathway of polyomavirus via ganglioside GD1a. J Virol 78:12259-67
Gilbert, Joanna M; Goldberg, Ilya G; Benjamin, Thomas L (2003) Cell penetration and trafficking of polyomavirus. J Virol 77:2615-22

Showing the most recent 10 out of 11 publications