Genetic architecture of host response to tickborne disease in Peromyscus leucopus

白鼠蜱传疾病宿主反应的遗传结构

• 批准号: 10625699
• 负责人: Alan G. Barbour
• 金额: $ 23.5万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625699
• 关键词: 3' Untranslated Regions; Administrative Supplement; Affinity; Agonist; Antibiotic Therapy; Antibodies; Antibody Response; Applications Grants; Attenuated; Bacteria; Basic Science; Biological; Borrelia burgdorferi; Characteristics; Clinical Research; Data; Deer Mouse; Development Plans; Disease; Fc Receptor; Funding; Genes; Genetic Engineering; Genomics; Immune response; Immunity; Immunization; Immunoglobulin G; Infection; Inflammation; Innate Immune Response; Innate Immune System; Investigation; Life Cycle Stages; Lipopolysaccharides; Lyme Disease; MHC Class II Genes; Mediating; NOS2A gene; Natural Immunity; New England; Nitric Oxide; Nitric Oxide Synthase; OspA protein; Patients; Peromyscus; Phagocytes; Phenotype; Population; Preparation; Production; Reactive Nitrogen Species; Research Support; Resources; Rodent; Tick-Borne Diseases; Tick-Borne Infections; Toll-like receptors; Translational Research; Untranslated Regions; Vaccines; Variant; Vector-transmitted infectious disease; Zoonoses; acquired immunity; arm; base; chronic infection; fitness; foot; forward genetics; genetic approach; genetic architecture; genetic variant; genome wide association study; inducible gene expression; knockout gene; macrophage; mutant; parent project; receptor; response; reverse genetics; tick transmission; trait; translational applications

PROJECT SUMMARY (Administrative supplement) For the administrative supplement a fourth specific aim is added to the project: Functional consequences of naturally-occurring genetic variants for responses of Peromyscus to Borreliella burgdorferi. The parent project principally entails forward genetics approaches to identify the traits and ultimately characterize the mechanisms for the white-footed deermouse's capacity to serve as a major reservoir for several zoonotic agents, including the cause of Lyme disease, while maintaining fitness in the presence of persistent infection. In the course of the project to date, we have made discoveries that justify a new line of investigation that takes a reverse genetics approach. The discoveries represent both innate and aquired immunity in Peromyscus immunity: (1) Structural variants in the Nos2 gene of P. leucopus populations that could account for an attenuated production of nitric oxide and reactive nitrogen species during infection. (2) Evidence in Peromyscus of an inactivated Fcgr1 gene that encodes the high-affinity IgG Fc receptor protein (FcγR1 or CD64) of macrophages and other phagocytes. (3) An association between a MHC class II gene and the antibody response to the OspA protein of Borreliella burgdorferi. The new aim comprises four sub- aims: (A) host response phenotypes of variants of the Nos2 gene and its 3’-UTR in P. leucopus, (B) functional effects of mutant Fcgr1 of Peromyscus, (C) variation of MHC II genes and antibodies to OspA after immunization, and (D) high-throughput discovery and annotation of structural variants segregating in the colony. The new research supported by this administrative supplement is anticipated to have both basic research and translational research and application impacts. The findings may also guide clinical research on persisting illness in patients with Lyme disease and other tickborne infections.

项目摘要（行政补充） 对于行政补充，该项目添加了第四个特定目标：功能 天然存在的遗传变异对peromyscus对伯氏伯氏菌的反应的后果。 父项目主要需要遗传学方法来识别这些特征，并最终 表征白脚Demer宫成为主要水库的能力的机制 几种人畜共患药，包括莱姆病的原因，同时保持适应性 持续感染。在迄今为止的项目过程中，我们已经发现了一条新线的发现 采用反向遗传学方法的调查。这些发现既代表先天又代表 peromyscus免疫的免疫力：（1）白假单胞菌种群NOS2基因中的结构变异 可以说明感染过程中一氧化氮和反应性氮的产生。 （2） 编码高亲和力IgG FC受体蛋白的灭活FCGR1基因的peromyscus的证据 （FcγR1或CD64）巨噬细胞和其他吞噬细胞。 （3）MHC II类基因之间的关联 以及对Borreliella burgdorferi的OSPA蛋白的抗体反应。新目标包括四个子 目的：（a）NOS2基因的变体及其3'-UTR的宿主响应表型，（b）功能 Peromyscus突变FCGR1的影响，（C）MHC II基因的变异和对OSPA抗体的变化。 免疫，（d）在隔离的结构变体的高通量发现和注释 殖民地。预计该行政补充支持的新研究将具有基本 研究和翻译研究和应用的影响。这些发现还可以指导有关的临床研究 莱姆病和其他tick虫感染患者的持续疾病。