Rhadinovirus Receptors - Structure, Signaling, and Cell Tropism

细胞受体是病原体嗜性的主要决定因素，并提供与宿主细胞的第一个特异性相互作用。人卡波西肉瘤相关疱疹病毒（KSHV）和恒河猴鼻状病毒（RRV）（KSHV的动物模型）均通过病毒gH/gL糖蛋白复合物结合受体酪氨酸激酶的Eph家族成员。A型受体EphA 2不仅对于感染KSHV至关重要，而且对于感染丙型肝炎病毒（HCV）、沙眼衣原体和疟疾寄生虫（病毒、细菌和真核生物来源的病原体）也至关重要。这种趋同的进化表明，与EphA 2的相互作用对于各种各样的病原体都是非常有利的，这就提出了一个问题：是什么让EphA 2如此有吸引力？考虑到这四种病原体的累积疾病负担，需要进一步分析。关于特定受体对RhadinovirusKSHV和RRV的细胞和组织嗜性的作用，我们的初步数据表明，除了Ephs之外，RRV的gH/gL还存在其他受体，并且很可能也是KSHV。特别是对于RRV，我们有强有力的证据表明Ephs和两种候选替代受体的细胞类型特异性使用。因此，拟议的研究集中在gH/gL受体相互作用的几个关键方面：a）病毒-受体相互作用的结构方面，特别是gH/gL-受体相互作用的晶体结构，以及单个相互作用对病毒进入和细胞向性的作用。B）新型受体和受体下游作用的宿主因子。对受体相互作用的结构基础和下游信号级联的新见解将允许设计新的干预策略，而不仅仅是KSHV。我们已经在利用我们对特定病毒-受体相互作用的初步但仍然有限的见解来产生缺乏与单个受体相互作用能力的突变病毒。我们将使用新的结构数据来完善这些突变体，我们将能够直接将新的结构信息与生物功能联系起来。我们的研究将为这些突变病毒作为疫苗和疫苗载体的未来应用奠定基础，这些病毒的细胞和组织嗜性是有限的，这是朝着预防性KSHV疫苗迈出的重要一步。

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.