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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要先天免疫基因的大效应突变会对传染病的易感性产生巨大影响此外，个体的更微妙和更广泛的变异的遗传决定因素。人们在许多病毒感染的突变背景下研究了对病毒感染的易感性和免疫反应。我们提出，存在由已知的先天免疫基因创建的新的多态性先天免疫基因。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，并且有能力调节个体的免疫反应。存在于每个人类基因组中，并且它们的数量和序列在人群中的个体之间有所不同。现在，旧的回溯在很大程度上被视为假基因而被忽视，而年轻的回溯已被由于最常见测序中固有的准确识别的技术挑战，尚未得到充分研究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基因组包含逆转录副本。 APOBEC3 病毒限制因子家族的成员，可转录并能够限制病毒复制我们最近的初步数据显示了其他抗病毒基因家族的广泛回顾。在人类和其他灵长类动物中，表明最近对病毒限制和宿主的回顾此外，依赖性因素可能很普遍，其中一些回顾还很年轻——仅存在于其中。一些人——并且可能代表了易感性个体差异的一个未被认识到的来源或结合计算生物学、体外病毒学和生物化学，以及高通量功能测定，我们将识别存在的病毒相互作用基因的年轻回顾仅在某些人类中进行测试，并测试这些新基因增强或阻碍先天免疫系统的能力为了检验我们的假设，即回溯扩展会改变免疫系统功能，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 (2)。表征多态性宿主依赖性和限制因子的转录和抗病毒功能 (3) 识别回溯，作为逃避病毒共同选择的限制因素或依赖因素。作为其亲代抗病毒基因的显性失活抑制剂，抑制先天免疫，从而产生免疫这项研究将发现新的先天免疫基因并发现新的病毒复制。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。