Viral Decoy Receptors

病毒诱饵受体

• 批准号: 7152884
• 负责人: Daved H. Fremont
• 金额: $ 29.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152884
• 关键词: Address; Baculoviruses; Binding; Binding Proteins; Biochemical; Bone Marrow; CCL2 gene; CD80 gene; Cells; Characteristics; Chemotaxis; Class; Complex; Crystallography; Cytokine Receptors; Development; Disease; Event; Facility Construction Funding Category; Family; Goals; Growth Factor; Hand; Homologous Gene; Human; Human Herpesvirus 4; Human herpesvirus 4 BARF1 protein; Immune; Immune response; Immunologic Surveillance; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Ligand Binding; Lymphocyte; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Mononuclear; Murine gammaherpesvirus M3 protein; Mus; Mutagenesis; Mutate; New Agents; Osteoclasts; Pathogenesis; Proteins; Recombinant Delta Chemokine; Research; Role; Specificity; Structure; Surface Plasmon Resonance; Testing; Thinking; Variant; Viral; Viral meningitis; Work; base; bindin; c-fms Proto-Oncogenes; chemokine; cytokine; design; extracellular; insight; macrophage; member; molecular recognition; mutant; novel; osteoclastogenesis; protein expression; receptor; receptor function

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.

拟议研究的目标是揭示病毒如何传播的结构和机制细节 诱饵受体的作用是实现免疫逃避。重点将放在两种伽玛疱疹病毒上 蛋白质，来自鼠伽马疱疹病毒 68 (MHV68) 的 M3 和来自 Epstein-Barr 病毒的 BARF1 （EBV）。这两种分泌蛋白被认为可以阻断宿主免疫监视机制 通过隔离炎症反应途径的关键细胞外介质。他们也是 由与具有相似功能的任何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，能够隔离所有四种趋化因子的成员 趋化细胞因子家族（CC、CXC、CX3C 和 C）中，BARF1 似乎具有高度特异性 为短链螺旋束细胞因子巨噬细胞集落刺激因子（CSF-1）。因此， 揭露他们的诡计机制将允许对混杂的比较 一方面是分子识别，另一方面是高度选择性的参与。这些目标 将通过使用细菌和杆状病毒介导的蛋白质进行实验解决 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。新的诱饵受体变体将在功能性研究中开发和研究 语境。对 M3 和 M3 采用的不同诱饵策略的详细机制理解 BARF1 应提供对趋化因子和细胞因子分子识别事件的见解 一般来说。此外，我们的实验结果可能会应用于控制 伽玛疱疹病毒的发病机制，并通过利用与这些诱饵受体类似的策略， 开发用于控制炎症性疾病的新药物。

项目成果

The chemokine binding protein M3 prevents diabetes induced by multiple low doses of streptozotocin.

趋化因子结合蛋白 M3 可预防多次低剂量链脲佐菌素诱发的糖尿病。

• DOI: 10.4049/jimmunol.178.7.4623
• 发表时间: 2007
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Martin,AndreaP;Alexander-Brett,JenniferM;Canasto-Chibuque,Claudia;Garin,Alexandre;Bromberg,JonathanS;Fremont,DavedH;Lira,SergioA
• 通讯作者: Lira,SergioA