Induction of NK-cell ligands by viruses

病毒诱导 NK 细胞配体

• 批准号: 7081707
• 负责人: DAVID H RAULET
• 金额: $ 28.99万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7081707
• 关键词: DNA damage; Herpesviridae; bioterrorism /chemical warfare; cell cell interaction; cell surface receptors; cellular immunity; cytokine; cytomegalovirus; disease /disorder model; fibroblasts; gene mutation; host organism interaction; human herpesvirus 8; human tissue; immunogenetics; immunoregulation; intravital microscopy; laboratory mouse; ligands; microorganism immunology; natural killer cells; parasite infection mechanism; toll like receptor; virus infection mechanism

Natural killer cells provide protection from numerous viruses in the early stages of the infection. NK cell activity is controlled by cytokines and cell surface stimulatory and inhibitory receptors. The NKG2D stimulatory receptor has been implicated in the recognition of cells infected with viruses. NKG2D recognizes the RAET1 (including several subfamilies) and MIC families of cell surface ligands, which are poorly expressed on the surface of most normal cells. MIC and RAET1 family members are transcriptionally upregulated in cells infected with herpesviruses and most likely other viruses. Our expertise on immune recognition by NK cells (Raulet) and viral immune evasion strategies (Coscoy) will be combined to investigate our hypothesis that viral infection leads to generic signals that upregulate transcription of NKG2D ligands, but that some viruses evade recognition by preventing ligand expression at the cell surface. The long term aim of these studies is to provide routes to develop therapeutic agents that enhance NK cell responses to viruses, especially in the context of biodefense. Our aims are to 1) focus on two herpesviruses to elucidate mechanisms that upregulate expression of NKG2D ligands in virus-infected cells, including the role of Toll like receptors, cytokines, interferons and the DNA damage pathway; 2) Examine representatives of 8 virus families, including several relevant to biofense, for their capacity to upregulate NKG2D ligand mRNAs and downregulate ligand proteins; by examining a panel of mutant fibroblasts defective in a broad array of protective functions, we expect to learn the factors responsible for ligand upregulation in different viral systems; 3) Determine how MHV68, a mouse gamma herpesvirus, evades NKG2D ligand upregulation, and, using two-photon microscopy, determine how NKG2D-ligand interactions impact NK cell-target cell interactions in vivo; 4) Determine whether the pathways uncovered in the mouse system in aims 1-3 regulate human NKG2D ligands in human cells infected with two herpesviruses, HCMV and KSHV. Importantly, aspects of this project will be part of a collaborative effort between the different groups participating in this PO1 application.

自然杀伤细胞在感染的早期阶段提供对许多病毒的保护。NK细胞 活性由细胞因子和细胞表面刺激性和抑制性受体控制。的nkg 2d 刺激性受体与病毒感染细胞的识别有关。NKG 2D识别 细胞表面配体的RAET 1（包括几个亚家族）和MIC家族，它们在细胞表面配体中的表达差， 在大多数正常细胞的表面表达。MIC和RAET 1家族成员在转录水平上是 在感染疱疹病毒和很可能其他病毒的细胞中上调。我们在免疫方面的专业知识 NK细胞的识别（Raulet）和病毒免疫逃避策略（Coscoy）将结合起来， 研究我们的假设，即病毒感染导致上调NKG 2D转录的通用信号 但是一些病毒通过阻止配体在细胞表面的表达来逃避识别。的 这些研究的长期目标是提供开发增强NK细胞的治疗剂的途径， 应对病毒，特别是在生物防御的背景下。我们的目标是：1）关注两种疱疹病毒 阐明在病毒感染细胞中上调NKG 2D配体表达的机制，包括 Toll样受体、细胞因子、干扰素和DNA损伤途径的作用; 2）检查代表性 8个病毒家族，包括几个与生物围栏相关的家族，因为它们能够上调NKG 2D配体 mRNA和下调配体蛋白;通过检查一组突变成纤维细胞缺陷，在广泛的 一系列的保护功能，我们希望了解不同的配体上调的因素， 病毒系统; 3）确定MHV 68，一种小鼠γ疱疹病毒，如何逃避NKG 2D配体上调， 并使用双光子显微镜，确定NKG 2D-配体相互作用如何影响NK细胞-靶细胞 4）确定目标1-3中小鼠系统中未发现的通路是否调节 在感染两种疱疹病毒HCMV和KSHV的人细胞中的人NKG 2D配体。重要的是， 该项目的各个方面将是参与该项目的不同团体之间合作努力的一部分。 PO 1应用程序。