Rhadinovirus Receptors - Structure, Signaling, and Cell Tropism

鼻病毒受体 - 结构、信号传导和细胞趋向性

• 批准号: 393153343
• 负责人: Dr. Alexander Hahn
• 金额: --
• 依托单位: Abteilung Infektionsbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/393153343?language=en
• 关键词: Rhadinovirus; Receptors; Structure; Signaling; Cell

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.

细胞受体是病原体趋向性的主要决定因素，并提供与宿主细胞的第一个特异性相互作用。人类卡波西肉瘤相关疱疹病毒 (KSHV) 和恒河猴病毒 (RRV)（KSHV 的动物模型）均通过病毒 gH/gL 糖蛋白复合物与受体酪氨酸激酶 Eph 家族的成员结合。 A 型受体 EphA2 不仅对于 KSHV 感染至关重要，而且对于丙型肝炎病毒 (HCV)、沙眼衣原体和疟疾寄生虫（病毒、细菌和真核来源的病原体）的感染也至关重要。这种趋同进化表明，与 EphA2 的相互作用对于多种病原体都极为有利，这就提出了一个问题：是什么让 EphA2 如此有吸引力？鉴于这四种病原体的累积疾病负担，需要进一步分析。关于鼻病毒KSHV和RRV的细胞和组织向性的特异性受体的作用，我们的初步数据表明除了Ephs之外还存在RRV的gH/gL的其他受体，并且很可能也存在KSHV的受体。特别是对于 RRV，我们有强有力的证据证明 Ephs 和两种候选替代受体的细胞类型特异性用途。因此，拟议的研究重点关注 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，以及个体相互作用对病毒进入和细胞向性的作用。b) 作用于受体下游的新型受体和宿主因子。对受体相互作用的结构基础和下游信号级联的新见解将有助于设计新的干预策略，而不仅仅是针对 KSHV。我们已经利用对特定病毒-受体相互作用的初步但仍然有限的见解来生成缺乏与单个受体相互作用的能力的突变病毒。我们将使用新的结构数据来完善这些突变体，并且我们将能够直接将新的结构信息与生物功能相关联。我们的研究将为这些突变病毒未来作为细胞和组织向性受到限制的疫苗和疫苗载体的应用奠定基础，这是迈向预防性 KSHV 疫苗的重要一步。

项目成果

A Recombinant Rhesus Monkey Rhadinovirus Deleted of Glycoprotein L Establishes Persistent Infection of Rhesus Macaques and Elicits Conventional T Cell Responses

删除糖蛋白 L 的重组恒河猴鼻病毒可建立恒河猴的持续感染并引发常规 T 细胞反应

• DOI: 10.1128/jvi.01093-19
• 发表时间: 2020
• 期刊: Journal of Virology
• 影响因子: 5.4
• 作者: Hahn AS;Bischof GF;Großkopf AK;Shin YC;Domingues A;Gonzalez-Nieto L;Rakasz EG;Watkins DI;Ensser A;Martins MA;Desrosiers RC
• 通讯作者: Desrosiers RC

Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV).

• DOI: 10.1371/journal.ppat.1008979
• 发表时间: 2021-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Großkopf AK;Schlagowski S;Fricke T;Ensser A;Desrosiers RC;Hahn AS
• 通讯作者: Hahn AS