Abstract

EBV is a causative agent in endemic Burkitt's 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 is also a factor in a variety of other human malignancies including some T-cell lymphomas, Hodgkin lymphoma, Burkitt's lymphoma, and gastric carcinoma. The pathologies 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 permissive for viral replication are of B cell origin. The major viral envelope glycoprotein 350 (gp350) binds to the complement receptor type two (CD21) that is abundantly expressed on B cells. Fusion of the virion membrane with the cell membrane minimally requires a complex of viral proteins that includes gB, gH, gL, 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.

Public Health Relevance

This proposed research represents a collaborative research program 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 and the proposed research may result in the identification of new therapeutics for EBV infections as well as the herpesvirus family in general of which EBV is a member.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076183-09
Application #
8044676
Study Section
Virology - B Study Section (VIRB)
Program Officer
Beisel, Christopher E
Project Start
2002-02-22
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
9
Fiscal Year
2011
Total Cost
$400,947
Indirect Cost

  Institution

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

  Publications

Chen, Jia; Sathiyamoorthy, Karthik; Zhang, Xianming et al. (2018) Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. Nat Microbiol 3:172-180
Möhl, Britta S; Chen, Jia; Park, Seo Jin et al. (2017) Epstein-Barr Virus Fusion with Epithelial Cells Triggered by gB Is Restricted by a gL Glycosylation Site. J Virol 91:
Sathiyamoorthy, Karthik; Jiang, Jiansen; Möhl, Britta S et al. (2017) Inhibition of EBV-mediated membrane fusion by anti-gHgL antibodies. Proc Natl Acad Sci U S A 114:E8703-E8710
Chen, Jia; Jardetzky, Theodore S; Longnecker, Richard (2016) The Cytoplasmic Tail Domain of Epstein-Barr Virus gH Regulates Membrane Fusion Activity through Altering gH Binding to gp42 and Epithelial Cell Attachment. MBio 7:
Möhl, Britta S; Schröter, Christina; Klupp, Barbara G et al. (2016) Comparative Mutagenesis of Pseudorabies Virus and Epstein-Barr Virus gH Identifies a Structural Determinant within Domain III of gH Required for Surface Expression and Entry Function. J Virol 90:2285-93
Möhl, Britta S; Chen, Jia; Sathiyamoorthy, Karthik et al. (2016) Structural and Mechanistic Insights into the Tropism of Epstein-Barr Virus. Mol Cells 39:286-91
Sathiyamoorthy, Karthik; Hu, Yao Xiong; Möhl, Britta S et al. (2016) Structural basis for Epstein-Barr virus host cell tropism mediated by gp42 and gHgL entry glycoproteins. Nat Commun 7:13557
Rowe, Cynthia L; Chen, Jia; Jardetzky, Theodore S et al. (2015) Membrane anchoring of Epstein-Barr virus gp42 inhibits fusion with B cells even with increased flexibility allowed by engineered spacers. MBio 6:
Sathiyamoorthy, Karthik; Jiang, Jiansen; Hu, Yao Xiong et al. (2014) Assembly and architecture of the EBV B cell entry triggering complex. PLoS Pathog 10:e1004309
Chen, Jia; Zhang, Xianming; Jardetzky, Theodore S et al. (2014) The Epstein-Barr virus (EBV) glycoprotein B cytoplasmic C-terminal tail domain regulates the energy requirement for EBV-induced membrane fusion. J Virol 88:11686-95

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