Rhadinovirus Receptors - Structure, Signaling, and Cell Tropism

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Cellular receptors are major determinants of pathogen tropism and provide the first specific interaction with the host cell. Both the human Kaposi's sarcoma-associated herpesvirus (KSHV) and the rhesus monkey rhadinovirus (RRV), an animal model for KSHV, bind members of the Eph family of receptor tyrosine kinases through the viral gH/gL glycoprotein complex. The A type receptor EphA2 is not only critical for infection with KSHV but also for infection with hepatitis C virus (HCV), Chlamydia trachomatis, and malaria parasites - pathogens of viral, bacterial, and eukaryotic origin. This convergent evolution suggests that interaction with EphA2 is extremely advantageous for a very diverse range of pathogens, which raises the question: What makes EphA2 so attractive? Given the cumulative disease burden of these four pathogens, further analysis is needed.With regard to the role of specific receptors for the cell and tissue tropism of the rhadinoviruses KSHV and RRV, our preliminary data indicate the existence of additional receptors other than Ephs for gH/gL of RRV, and very likely also for KSHV. For RRV in particular, we have strong evidence for cell type-specific use of Ephs and two candidate alternative receptors. The proposed research therefore focuses on several key aspects of the gH/gL receptor interaction:a) Structural aspects of virus-receptor interactions, in particular crystal structures of the gH/gL-receptor interaction, and the role of individual interactions for viral entry and cell tropism.b) Novel receptors and host factors acting downstream of receptors. New insights into the structural basis of receptor interactions and into downstream signaling cascades will allow devising novel intervention strategies, not only for KSHV. We are already using our preliminary but still limited insights about specific virus-receptor interactions to generate mutant viruses that lack the ability to interact with individual receptors. We will use novel structural data to refine these mutants, and we will be able to directly correlate novel structural information with biological function. Our research will lay the groundwork for future application of these mutant viruses as vaccines and vaccine vectors whose cell and tissue tropism is restricted, an important step towards a prophylactic KSHV vaccine.