Reverse transcriptase-mediated expansion of the host innate immune system

逆转录酶介导的宿主先天免疫系统扩张

• 批准号: 10574416
• 负责人: Richard Noel McLaughlin
• 金额: $ 23万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-12 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574416
• 关键词: APOCEC3G gene; Alleles; Animals; Antiviral Response; Back; Binding; Biochemistry; Biological Assay; Birth; Cebidae; Cells; Communicable Diseases; Computational Biology; Data; Dependence; Dimerization; Disease Outcome; Disease susceptibility; Disparate; Dominant-Negative Mutation; EEF1A1 gene; Elongation Factor; Exons; Expression Profiling; Family; Frequencies; Gene Duplication; Gene Family; Genes; Genetic Determinism; Genetic Polymorphism; Genetic Transcription; Genome; Haploidy; Haplotypes; Heritability; Human; Human Genome; Immune; Immune response; Immunity; In Vitro; Individual; Innate Immune System; Interferons; Invaded; Knock-out; Link; Location; Maps; Measures; Mediating; Messenger RNA; Mutation; Natural Immunity; Outcome; Peptide Fragments; Peptides; Phase; Pongidae; Population; Predisposition; Primates; Process; Proteins; Pseudogenes; Publishing; RNA Viruses; RNA-Directed DNA Polymerase; Recording of previous events; Research; Resistance; Retroviridae; Retroviridae Infections; Reverse Transcription; Role; Shapes; Signal Transduction; Source; Technology; Testing; Tissues; Translating; Translations; Variant; Viral; Viral Genes; Viral Physiology; Virus; Virus Diseases; Virus Replication; cell type; cofactor; dimer; gene interaction; genome analysis; high throughput screening; human reference genome; immune system function; individual variation; inhibitor; innate immune function; insertion/deletion mutation; pathogen; promoter; prospective; transcription factor; virology

PROJECT SUMMARY Large effect mutations in innate immunity genes can have dramatic effects on infectious disease susceptibility and outcome. In addition, the genetic determinants of more subtle and widespread variation in an individual’s susceptibility and immune response to viral infections has been studied in the context of mutations in the many known innate immunity genes. We propose that there are new polymorphic innate immune genes created by retroviruses (so called ‘retrocopies’) in the genome of many individuals which are typically overlooked, and which have the capacity to modulate an individual’s immune response. Thousands of young and old retrocopies are present in each human genome and their number and sequences differ among individuals in a population. Until now, old retrocopies have largely been ignored as pseudogenes, while young retrocopies have been understudied due to technical challenges of accurate identification inherent in the most common sequencing technologies. A pioneering study in our lab showed that human and other primate genomes contain retrocopies of the APOBEC3 family of viral restriction factors that are transcribed and capable of restricting virus replication in vitro. Our more recent preliminary data revealed extensive retrocopying of additional antiviral gene families within humans and other primate species, suggesting the recent retrocopying of viral restriction and host dependency factors may be widespread. Further, some of these retrocopies are very young – present in only some humans – and could represent an unappreciated source of individual variation in susceptibility or resistance to viral infection. With a combination of computational biology, in vitro virology and biochemistry, and high throughput functional assays, we will identify young retrocopies of virus-interacting genes that are present in only some humans and test these new genes’ ability to enhance or impede the innate immune system’s antiviral response. To test our hypothesis that retrocopy expansions modify immune system function, we will: (1) Identify young, polymorphic retrocopies of host dependency and restriction factor genes in humans. (2) Characterize transcription and antiviral functions of polymorphic host dependency and restriction factor retrocopies, either as restriction factors or dependency factors that evade viral co-option. (3) Identify retrocopies that act as dominant negative inhibitors of their parental antiviral genes thereby inhibiting the innate immune system and promoting viral replication. This research will discover new innate immune genes and found a new direction in understanding the genetic determinants of an individual's susceptibility and immune response to virus infection.

项目总结 先天免疫基因的大效应突变可能会对传染病易感性产生重大影响 和结果。此外，个体中更微妙和更广泛的变异的遗传决定因素 对病毒感染的易感性和免疫反应已经在许多基因突变的背景下进行了研究 已知的先天免疫基因。我们认为存在新的多态先天免疫基因，这些基因由 许多个体基因组中的逆转录病毒(所谓的逆转录病毒)，通常被忽视，而且 具有调节个体免疫反应的能力。数以千计的年轻和年老的复制品 存在于每个人类基因组中，它们的数量和序列在种群中的个体之间是不同的。直到 现在，旧的逆转录本在很大程度上被认为是假基因而被忽视，而年轻的逆转录本则被忽视了 由于最常见的测序中固有的准确识别的技术挑战，研究不足 技术。我们实验室的一项开创性研究表明，人类和其他灵长类动物的基因组含有逆转录本。 APOBEC3家族的病毒限制因子，可转录并能限制病毒复制 在试管中。我们最新的初步数据显示，更多的抗病毒基因家族存在广泛的逆转录复制 在人类和其他灵长类物种中，表明最近病毒限制和宿主的逆转录复制 依赖因素可能很普遍。此外，这些复制件中的一些非常年轻--只存在于 一些人类--可能代表着个体易感性变异的未知来源 对病毒感染的抵抗力结合了计算生物学、体外病毒学和生物化学，以及 高通量功能分析，我们将识别存在的病毒相互作用基因的年轻逆转录本 并测试这些新基因增强或阻碍先天免疫系统的能力 抗病毒反应。为了验证我们的假设，即逆转录扩增可以改变免疫系统功能，我们将：(1) 鉴定人类宿主依赖和限制因子基因的年轻的、多态的逆转录拷贝。(2) 多态宿主依赖和限制因子的转录和抗病毒功能研究 逆转录，或者作为限制因素，或者作为逃避病毒选择的依赖因素。(3)识别复制件 作为父母抗病毒基因的显性负抑制物，从而抑制先天免疫 系统和促进病毒复制。这项研究将发现新的先天免疫基因，并发现新的 了解个体易感性和免疫反应的遗传决定因素的方向 病毒感染。