This proposal represents a collaborative project between Dr. Longnecker and Dr. Jardetzky to define the molecular mechanisms involved in Epstein-Barr virus (EBV) entry into B lymphocytes, the major target cell of EBV in human hosts. EBV is associated with a variety of hematopoietic, epithelial, and lymphoproliferative diseases. EBV causes infectious mononucleosis in adolescents and is known to play an etiological role in human malignancies. EBV is a causative agent in endemic Burkitts lymphoma and undifferentiated nasopharyngeal carcinoma (NPC). EBV is also recognized as an important pathogen in immunosuppressed individuals, causing a variety of proliferative disorders including immunoblastic lymphomas, oral hairy leukoplakia, and an unusual tumor of muscle origin in immunosuppressed children. EBV may also be a factor in a variety of other human malignancies including some T-cell lymphomas, Hodgkin's Disease, and breast cancer. These disorders suggest a wide variety of tissue tropism for EBV in vivo. In vitro and in vivo, the cells that are most susceptible to EBV infection and most permissive for viral replication are of B cell origin. The major viral envelope glycoprotein 350 (gp350) binds to the complement receptor type two (CD21) which is abundantly expressed on B cells. Fusion of the virion membrane with the cell membrane minimally requires a complex of viral proteins that includes gp85, gp25, and gp42. Gp42 has been specifically found to bind to human leukocyte antigen (HLA) class II and this interaction is required for EBV entry into B lymphocytes. To date, little is known about the mechanism that EBV uses to bind and penetrate B cells. This proposal will analyze the role of gp42 and its interaction with HLA for viral entry by structure-function studies. Clarifying the interactions between cellular receptors and viral glycoproteins is essential for understanding the tropisms behind EBV associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093444-05
Application #
6998418
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Wong, May
Project Start
2002-02-22
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
5
Fiscal Year
2006
Total Cost
$365,107
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Garcia, Nicholas J; Chen, Jia; Longnecker, Richard (2013) Modulation of Epstein-Barr virus glycoprotein B (gB) fusion activity by the gB cytoplasmic tail domain. MBio 4:e00571-12
Chen, Jia; Jardetzky, Theodore S; Longnecker, Richard (2013) The large groove found in the gH/gL structure is an important functional domain for Epstein-Barr virus fusion. J Virol 87:3620-7
Connolly, Sarah A; Jackson, Julia O; Jardetzky, Theodore S et al. (2011) Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol 9:369-81
Rowe, Cynthia L; Matsuura, Hisae; Jardetzky, Theodore S et al. (2011) Investigation of the function of the putative self-association site of Epstein-Barr virus (EBV) glycoprotein 42 (gp42). Virology 415:122-31
Kirschner, Austin N; Sorem, Jessica; Longnecker, Richard et al. (2009) Structure of Epstein-Barr virus glycoprotein 42 suggests a mechanism for triggering receptor-activated virus entry. Structure 17:223-33
Anderson, Leah J; Longnecker, Richard (2008) An auto-regulatory loop for EBV LMP2A involves activation of Notch. Virology 371:257-66
Omerovic, Jasmina; Longnecker, Richard (2007) Functional homology of gHs and gLs from EBV-related gamma-herpesviruses for EBV-induced membrane fusion. Virology 365:157-65
Backovic, Marija; Leser, George P; Lamb, Robert A et al. (2007) Characterization of EBV gB indicates properties of both class I and class II viral fusion proteins. Virology 368:102-13
Swanson-Mungerson, Michelle; Longnecker, Richard (2007) Epstein-Barr virus latent membrane protein 2A and autoimmunity. Trends Immunol 28:213-8
Backovic, Marija; Jardetzky, Theodore S; Longnecker, Richard (2007) Hydrophobic residues that form putative fusion loops of Epstein-Barr virus glycoprotein B are critical for fusion activity. J Virol 81:9596-600

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