Molecular study of mouse viral resistance mechanisms

小鼠病毒抵抗机制的分子研究

• 批准号: 7769918
• 负责人: Michael G Brown
• 金额: $ 35.44万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769918
• 关键词: Acute; Alleles; Antiviral Agents; Backcrossings; Biochemical; Biological Assay; Breeding; C57BL/6 Mouse; Candidate Disease Gene; Cell-Mediated Cytolysis; Cells; Chromosomes; Complex; Congenic Strain; Consensus; Cytolysis; Cytomegalovirus; Cytomegalovirus Infections; DNA Viruses; Data; Defense Mechanisms; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Head; Herpesviridae; Histocompatibility Antigens Class II; Homologous Gene; Host Defense; Human; Hybrids; Immune; Immunity; Inbred BALB C Mice; Individual; Infection; International; Laboratories; Ligands; Link; Location; Mediating; Molecular; Murid herpesvirus 1; Mus; NZW Mouse; Natural Immunity; Natural Killer Cells; Operating System; Play; Predisposition; Proteins; Publishing; Quantitative Genetics; RNA; Receptor Activation; Recurrence; Research Personnel; Research Proposals; Resistance; Resolution; Role; Staining method; Stains; System; Testing; Time; Uncertainty; Universities; Variant; Viral; Virginia; Virus; Virus Diseases; adaptive immunity; base; genetic strain; genome-wide; member; offspring; pathogen; phenome; programs; prospective; receptor; resistance mechanism; trait; viral resistance

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.

众所周知，NK细胞具有识别和裂解病毒感染细胞的能力。事实上， 缺乏NK细胞免疫力的人类和小鼠很容易患上压倒性和复发性疱疹 病毒感染。在C57 BL/6小鼠中，宿主抗鼠巨细胞病毒（MCMV）免疫需要NK细胞 在MCMV感染的细胞上表达其病毒编码的m157配体的Ly 49 H活化受体识别。 然而，我们最近发现NZW小鼠中的NK细胞在控制实验性MCMV感染方面没有作用。 对于Ly 49 H + NK细胞。在此，我们扩展了我们在MA/My小鼠中的发现。MA/My菌株值得注意 因为它也显示出非常有效的NK细胞介导的MCMV感染控制，但该菌株中的NK细胞 不表达Ly 49 H受体。有趣的是，MA/My中的MCMV耐药性与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 它们的区别在于遗传多态性。因此，本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发挥不同的作用， 在感染后的早期迅速识别和破坏病毒病原体， 控制宿主防御的机制本文的具体目标将首先侧重于识别 和表征宿主基因，所述宿主基因通过以下途径对先天性抗MCMV免疫有实质性贡献： 经典孟德尔遗传学研究该方法是基于杂交种的快速表型表征 实验MCMV感染后的后代和随后的全基因组基因型鉴定， 单独的.使用这种高通量遗传学策略，染色体位置将在 定量遗传学策略，在间隔特异性同源菌株中得到证实， 将在前瞻性分子和生物化学分析中评估基因。为了便于识别宿主 病毒抗性基因，我们还将研究NK细胞识别病毒感染的细胞毒性 检测和病毒株变异选择也将用于了解宿主的先天防御 机械地。虽然NK细胞采用多种防御机制立即控制病毒病原体， 在感染后和适应性免疫能力增强之前，我们的研究无疑将具有重要意义。 人类先天防御CMV和潜在的其他病毒感染的影响。