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.
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.
|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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