Gammaherpesvirus pathogenesis: role of heparan sulfate in vivo

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DESCRIPTION (provided by applicant): The human gammaherpesvirus Kaposi's Sarcoma associated Herpesvirus (KSHV) is the causative agent of a skin cancer, Kaposi's Sarcoma, and certain AIDS-associated lymphoproliferative disorders. MHV68 is a murine gammaherpesvirus that shares biological features and sequence homology with KSHV and provides an excellent mouse model in which host-gammaherpesvirus interactions can be studied. Like KSHV, MHV68 is critically dependent on the presence of heparan sulfate (HS) at the cell surface to infect its target cells. Surprisingly, while B cells represent the main viral reservoir for KSHV and MHV68 in vivo, these cells do not express HS at their surface. How can these viruses infect B cells, while this cell type lacks a major viral coreceptor? We have found that HS was rapidly upregulated on B cells in the first hours following MHV68 injection in mice. This effect was mediated by the action of type-I interferon (IFN-I), a cytokine produced early upon infection as part of the innate immune response. Our findings suggest the following model: MHV68 first interacts with dendritic cells, which in turn produce IFN-I; IFN-I induces an upregulation of HS at the surface of B cells, rendering them permissive to infection. The fact that a virus can take advantage of the interferon response is a completely novel and unexpected finding. Here we propose experiments to validate our model (Aim1) and characterize the molecular mechanisms of HS upregulation on B cells upon exposure to type-I interferon (Aim2). Finding the molecular mechanisms of HS induction in B cells might provide useful information for the design of drugs aimed at limiting KSHV propagation in immunocompromised patients. Although many viruses are known to use HS to infect their target cells, our work is, to our knowledge, the first study examining the role of HS in viral pathogenesis in vivo, and in particular, to show that HS expression is tightly regulated in the context of an infection. Importantly, IFN-I is produced in most cases of viral and bacterial infections and thus our findings that HS is upregulated on B cells can almost certainly be extended to numerous pathogens. Heparan sulfate binds growth factors, cytokines and chemokines, influencing numerous biological processes. Thus, we believe that the upregulation of HS on B cells upon IFN-I production has important consequences on the biology of these cells and ultimately on the ability to mount a robust immune response. Our long-term objectives are to study the direct impact of our findings on the field of immunology and infectious disease. PUBLIC HEALTH RELEVANCE: Kaposi's Sarcoma associated Herpesvirus (KSHV) is a gammaherpesvirus that causes cancers in humans. This virus does not infect mice nor does it infect cells in culture efficiently. Murine gammaherpesvirus 68 (MHV68) is a closely related virus that is used as a model to study gammaherpesvirus pathogenesis both in cell culture systems and in mice. Like many viruses, KHSV and MHV68 use heparan sulfate (HS) as a coreceptor to enter into their target cells. However, while B cells are the main type of cells infected in vivo, we observed that these cells do not normally express HS at their surface. The purpose of our work is to understand how these viruses can infect B cells while this cell type lacks a major molecule necessary for viral entry. In our preliminary study, we found that MHV68 has found a very unexpected way to trigger HS expression at the B cell surface. In the first hours following MHV68 injection, mice produce type-I interferon as part of the normal antiviral response. We found that this type-I interferon production triggers HS expression at the B cell surface, thus rendering these cells potentially permissive to the infection. Here we propose experiments to validate our model and understand the molecular mechanisms that control these events.