Molecular study of mouse viral resistance mechanisms

NK细胞是众所周知的识别和裂解病毒感染细胞的能力。事实上，东道主在中国的防御 缺乏NK细胞免疫的人类和小鼠很容易患上铺天盖地和反复发作的疱疹 病毒感染。在C57BL/6小鼠中，宿主抗小鼠巨细胞病毒(MCMV)免疫需要NK细胞 在感染MCMV的细胞上表达其病毒编码的M157配体的Ly49H激活受体识别。 我们最近发现，NZW小鼠的NK细胞对实验性的MCMV感染没有控制作用 对于Ly49H+NK细胞。在此，我们在MA/My小鼠中扩展了我们的发现。MA/MY的品系值得注意 因为它也表现出非常有效的NK细胞介导的MCMV感染控制，但该菌株中的NK细胞 不表达Ly49H受体。有趣的是，MA/MY中的MCMV抗性与MHC密切相关 以及非MHC基因。因此，我们发现NK细胞利用多种抗病毒控制机制 以基因多态来区分。因此，这项研究提案的长期目标 是为了了解宿主基因的遗传变异如何在先天免疫中做出不同的贡献，其能力 在感染后的早期迅速识别和消灭病毒病原体以及分子和细胞 控制这种宿主防御的机制。这里的具体目标最初将集中在识别 以及宿主基因的特性，这些基因通过以下途径对天然抗MCMV免疫做出重大贡献 经典孟德尔遗传学研究。该方法基于杂交种的快速表型特征 实验性MCMV感染后的后代及其随后的全基因组基因型别鉴定 个人的。使用这种高通量遗传学策略，染色体位置将在 数量遗传学策略，在区间特异的同源品系中得到证实，随后成为候选 基因将在未来的分子和生化分析中进行评估。以便于识别主机 病毒耐药基因，我们还将研究NK细胞识别病毒感染的细胞毒性 化验和病毒株变异选择也将被用来了解宿主的天然防御。 从机械上讲。而NK细胞使用多种防御机制来立即控制病毒病原体 在感染之后，在适应性免疫发挥作用之前，我们的研究无疑将具有重要的意义 对人类在巨细胞病毒和潜在的其他病毒感染中的先天防御的影响。

NK cells are well known for the capacity to recognize and lyse virus infected cells. Indeed, host defenses in humans and mice that lack NK cell immunity are quite vulnerable to overwhelming and recurrent Herpes virus infections. In C57BL/6 mice, host anti-murine cytomegalovirus (MCMV) immunity requires NK cell expressed Ly49H activation receptor recognition of its virus encoded m157 ligand on MCMV infected cells. We recently showed that NK cells in NZW mice however, control experimental MCMV infection without a role for Ly49H+ NK cells. Herein we have extended our finding in MA/My mice. The MA/My strain is noteworthy since it also displays very effective NK cell-mediated control of MCMV infection, but NK cells in this strain do not express Ly49H receptors. Interestingly, MCMV resistance in MA/My is strongly associated with MHC and also non MHC genes. Thus, we have found that NK cells utilize multiple antiviral control mechanisms that are distinguished by genetic polymorphism. The long-term objective of this research proposal therefore is to understand how genetic variation in host genes can contribute differently in innate immunity, its capacity to rapidly recognize and destroy viral pathogens at early times after infection and the molecular and cellular mechanisms controlling such host defenses. The Specific Aims herein will focus initially on the identification and characterization of host genes that contribute substantially to innate anti-MCMV immunity through classical Mendelian genetics studies. The approach is based on rapid phenotypic characterization of hybrid offspring after experimental MCMV infection and subsequent genome-wide genotypic identification of each individual. Using this high-throughput genetics strategy, chromosome locations will be identified in quantitative genetics strategies, confirmed in interval-specific congenic strains, and subsequently candidate genes will be assessed in prospective molecular and biochemical analyses. To facilitate identification of host virus resistance genes, we will also investigate NK cell recognition of virus infection in cellular cytotoxicity assays and virus strain variant selection will also be used to understand innate host defenses mechanistically. While NK cells employ multiple defense mechanisms to control viral pathogens immediately after infection and before adaptive immunity is competent, our studies will no doubt have important implications for human innate defenses in CMV and potentially other virus infections.