This proposal represents a close collaborative effort between the Jardetzky and Longnecker laboratories focusing on understanding Epstein-Barr virus (EBV) entry into target cells and in particular defining how receptor binding triggers fusion mediated by EBV-encoded glycoproteins. EBV is a causative agent in endemic Burkitt's lymphoma, Hodgkin's lymphoma, and undifferentiated nasopharyngeal carcinoma (NPC). EBV is also recognized as an important pathogen in immunosuppressed individuals including HIV/AIDS patients causing a variety of proliferative disorders such as immunoblastic lymphomas, oral hairy leukoplakia, and other pathologies. Fusion of EBV with a cellular membrane minimally requires a complex of viral proteins that includes gB, gH/gL, and gp42 for B cells and gB and gH/gL for epithelial cells. In the previous funding period, we made substantial progress in understanding how EBV as well as other herpesviruses bind to and ultimately fuse with target cells. In the past funding period, we solved three key structures - gp42 alone, which allowed comparison to our previous structure of gp42 bound to the receptor HLA, gH/gL, and the post fusion form of gB. In addition, in the previous funding period, we began to identify functional domains of these key glycoproteins providing considerable momentum to our proposed studies in the new funding period. Overall, in our two aims, we plan to elucidate how receptor binding to EBV triggers changes in viral glycoprotein interactions that ultimately result in refolding of gB and fusion of the virion envelope with a cellular membrane. Clarifying the interactions between cellular receptors and viral glycoproteins, and the steps that lead from receptor binding to membrane fusion, 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 and epithelial cells - the major cellular targets of EBV infection in human hosts. EBV is associated with a variety of hematopoietic, epithelial, and lymphoproliferative diseases and the proposed research will lead to a better understanding of EBV and herpesvirus entry in general and may result in the identification of new targets for herpesvirus therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI076183-11
Application #
8503993
Study Section
Virology - A Study Section (VIRA)
Program Officer
Beisel, Christopher E
Project Start
2002-02-22
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
11
Fiscal Year
2013
Total Cost
$490,755
Indirect Cost
$90,830
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
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
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
Möhl, Britta S; Sathiyamoorthy, Karthik; Jardetzky, Theodore S et al. (2014) The conserved disulfide bond within domain II of Epstein-Barr virus gH has divergent roles in membrane fusion with epithelial cells and B cells. J Virol 88:13570-9
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
Rowe, Cynthia L; Connolly, Sarah A; Chen, Jia et al. (2013) A soluble form of Epstein-Barr virus gH/gL inhibits EBV-induced membrane fusion and does not function in fusion. Virology 436:118-26
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
Chen, Jia; Rowe, Cynthia L; Jardetzky, Theodore S et al. (2012) The KGD motif of Epstein-Barr virus gH/gL is bifunctional, orchestrating infection of B cells and epithelial cells. MBio 3:
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
Plate, Aileen E; Reimer, Jessica J; Jardetzky, Theodore S et al. (2011) Mapping regions of Epstein-Barr virus (EBV) glycoprotein B (gB) important for fusion function with gH/gL. Virology 413:26-38
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

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