Molecular and cellular mechanisms of synapse-mediated spread of Epstein Barr virus: overcoming the CD21-restricted cellular tropism.

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Epstein Barr Virus (EBV) is a common, orally-transmitted virus, infecting most of the human population. EBV maintains a silent infection for the lifetime of the host by hiding in a subset of lymphocytes called B cells. EBV infection of B cells in the laboratory has been extensively studied. In the laboratory, infected B cells are efficiently transformed into continuously growing cells with the potential to cause cancer. This happens only rarely in the body, but when it does can cause B cell cancers including Hodgkin lymphoma. One reason why B cell cancers are so rare is because infection is kept under control by immune responses involving other cells, including T and natural killer (NK) cells.The mechanisms of EBV entry into B cells have been extensively studied. Proteins on the virus (gp350 and gp42) interact with virus receptors on the cell surface (CD21, HLA class II respectively) to bind the EBV to the B cell. Thereafter further virus proteins (gp82, gp25) trigger virus internalisation. However, infection of other cell types, including epithelial, T and NK cells that do not express the CD21 are also observed. These infections are associated with either virus transmission to a new susceptible host (epithelial), or are associated with diseases and malignancies of epithelial, T and NK cells.Epithelial cells line the oral cavity (oropharynx) and create a barrier for entry of EBV into an uninfected host, and for escape of EBV from an infected host for transmission to a new susceptible host. Epithelial cells are thought to be the major site of EBV replication in the oropharynx; however they do not express CD21, and EBV infection of epithelial cells in the laboratory is poor. I have previously shown that infection of epithelial cells can be greatly enhanced by first binding the virus to B cells. EBV binding to CD21 triggers adhesion molecules and EBV on the B cell surface to polarise then 'adhere' to the epithelial cells, bringing EBV into close contact with epithelial cells and enabling efficient infection. This process is probably similar to the situation in the oropharynx, where epithelial cells and lymphocytes, including B cells, are in close contact with each other.In our model of EBV infection of epithelial cells, we suggest EBV on the B cells may come from fully matured B cells, called plasma cells, which when infected with EBV produce new infectious virus. This EBV may be released from the plasma cell to interact with the resting B cell as above. Or, as increasingly observed with other viruses that infect lymphocytes (like HIV), the plasma cell may interact directly with the epithelial cell, cause EBV inside the plasma cell to relocate to the point of cell-to-cell contact and transmit directly from the plasma cell to the epithelial cell, thereby evading anti-EBV antibodies. Here, I intend to extend my studies to understand how EBV can infect epithelial cells using plasma cells as the virus donor, and determine the molecular requirements of epithelial cells and EBV for efficient infection, so we can understand how to disrupt EBV transmission with vaccines.EBV associated T and NK cell diseases range from illnesses that appear to be a consequence of an over-active immune system (EBV-associated haemophagocytic lymphohistiocytosis, chronic active EBV), to aggressive malignancies (extranodal T/NK cell lymphoma, aggressive NK cell leukaemia).T and NK cells do not express CD21 and we do not understand how these cells can be infected with EBV. Using two different methods, I aim to determine how infection of these cells is achieved: (1) Using plasma cell interaction with T and NK cells, and (2) infecting CD21-positive immature T and NK cells. With this new information, we will be able to develop ideas of how the virus may be causing the T and NK cell diseases, and begin develop new treatments for these treatment-resistant diseases.