Viral Decoy Receptors

这项拟议的研究的目标是揭示病毒如何在结构和机制上的细节 诱饵受体的功能是实现免疫逃避。重点将放在两种伽马疱疹病毒上 小鼠疱疹病毒68的M3蛋白和EB病毒的BARF1蛋白 (EBV)。这两种分泌的蛋白质都被认为可以阻止宿主的免疫监视机制。 通过隔离炎症反应途径的关键细胞外介质。他们也是 由与任何具有相似功能的已知宿主蛋白无关的新序列编码。而M3 是一种广谱趋化因子结合蛋白，能够隔离所有四个成员 趋化细胞因子家族(CC、CXC、CX3C和C)，BARF1似乎具有高度特异性 短链螺旋束细胞因子巨噬细胞集落刺激因子(CSF-1)。因此， 揭开他们的诡计机制将允许比较乱交 一方面是分子识别，另一方面是高度选择性的接触。这些目标 将通过使用细菌和杆状病毒介导的蛋白在实验中解决 表达、X射线结晶学、生物物理相互作用分析和基于结构的分子 设计。将开发和研究新的诱骗受体变体 背景。对M3和M3采用的不同诱骗策略的详细机械理解 BARF1应提供对趋化因子和细胞因子分子识别事件的见解 一般说来。此外，我们的实验结果可能会在控制中得到应用 伽马疱疹病毒的发病机制，并通过利用与这些诱骗受体类似的策略， 用于控制炎症紊乱的新药物的开发。

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 gammaherpesvirus68 (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.