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.

项目摘要 先天免疫基因的大效应突变对感染性疾病的易感性有显著影响 和结果。此外，在一个人的基因中， 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提出，有新的多态性先天免疫基因的创造， 逆转录病毒（所谓的“逆转录病毒”）在许多人的基因组中通常被忽视， 有能力调节个体的免疫反应。数以千计的年轻人和老年人 存在于每个人类基因组中，并且它们的数量和序列在群体中的个体之间不同。直到 现在，旧的逆转录复制物在很大程度上被当作假基因而被忽视，而年轻的逆转录复制物则被认为是假基因。 由于在最常见的测序中固有的准确鉴定的技术挑战， 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中含有逆转录病毒， 转录并能够限制病毒复制的病毒限制因子的APOBEC 3家族 体外我们最近的初步数据揭示了额外的抗病毒基因家族的广泛的逆转录 在人类和其他灵长类动物物种中，这表明最近病毒限制和宿主 依赖性因素可能很普遍。此外，其中一些复刻是非常年轻的-目前只有在 一些人-并且可能代表易感性个体差异的未被认识的来源， 抵抗病毒感染。结合计算生物学、体外病毒学和生物化学， 高通量功能测定，我们将确定年轻的逆转录病毒相互作用基因， 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，即逆转录扩增改变免疫系统功能，我们将：（1） 识别人类宿主依赖性和限制因子基因的年轻多态性逆转录。（二） 多态性宿主依赖性和限制性因子的转录和抗病毒功能 逆转录，无论是作为限制因素或依赖性因素，逃避病毒的共同选择。(3)识别追溯副本 其作为其亲本抗病毒基因的显性负抑制剂，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， 在理解一个人的易感性和免疫反应的遗传决定因素的方向， 病毒感染。