Viral Decoy Receptors

描述（由申请人提供）：拟议研究的目标是揭示病毒诱饵受体如何发挥功能以实现免疫逃避的结构和机制细节。重点将放在两个γ疱疹病毒蛋白，M3从鼠γ疱疹病毒68（MHV 68）和BARF 1从EB病毒（EBV）。这两种分泌蛋白被认为通过隔离炎症反应途径的关键细胞外介质来阻断宿主免疫监视机制。它们也由与具有类似功能的任何已知宿主蛋白无关的新序列编码。虽然M3是一种广谱趋化因子结合蛋白，能够隔离所有四种趋化因子家族（CC，CXC，CX 3C和C）的成员，但BARF 1似乎对短链螺旋束细胞因子巨噬细胞集落刺激因子（CSF-1）具有高度特异性。因此，揭开它们的托辞机制将允许一方面比较混杂的分子识别，另一方面比较高度选择性的接合。这些目标将通过使用细菌和杆状病毒介导的蛋白质表达，X射线晶体学，生物物理相互作用分析和基于结构的分子设计来解决。新型诱饵受体变体将在功能背景下开发和研究。M3和BARF 1所采用的不同诱饵策略的详细机制理解应该提供对趋化因子和细胞因子分子识别事件的见解。此外，我们的实验结果可能会发现应用在控制γ疱疹病毒的发病机制，并通过利用类似的策略，这些诱饵受体，开发新的药物控制炎症性疾病。

DESCRIPTION (provided by applicant): The goal of the proposed research is to reveal structural and mechanistic details of how viral decoy receptors function to enable immune evasion. The focus will be on two gammaherpesvirus proteins, M3 from murine gammaherpesvirus 68 (MHV68) and BARF1 from Epstein-Barr virus (EBV). Both of these secreted proteins are thought to block host immune surveillance mechanisms by sequestering key extracellular mediators of inflammatory response pathways. They are also encoded by novel sequences unrelated to any known host proteins with similar functions. While M3 is a broad-spectrum chemokine binding protein, able to sequester members of all four chemoattractant cytokine families (CC, CXC, CX3C, and C), BARF1 appears to be highly specific for the short-chain helical-bundle cytokine macrophage colony-stimulating factor (CSF-1). Thus, the unmasking of their subterfuge mechanisms will allow for the comparison of promiscuous molecular recognition on the one hand, and highly selective engagement on the other. These aims will be addressed experimentally through the use of bacterial and baculovirus mediated protein expression, x-ray crystallography, biophysical interaction analysis, and structure-based molecular design. Novel decoy receptor variants will be developed and investigated within a functional context. A detailed mechanistic understanding of the distinct decoy strategies employed by M3 and BARF1 should provide insights into chemokine and cytokine molecular recognition events generally. Further, our experimental results may find application in the control of gammaherpesvirus pathogenesis and, by exploiting similar strategies as these decoy receptors, the development of new agents for the control of inflammatory disorders.