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） 在行政补充方面，该项目增加了第四个具体目标： 自然发生的遗传变异对Peromyscus对Borreliella burgdorferi反应的影响。 母项目主要需要正向遗传学方法来识别性状，并最终 描述了白足鹿鼠作为主要水库的能力的机制， 几个人畜共患病的代理人，包括莱姆病的原因，同时保持健身的存在， 持续感染在迄今为止的项目过程中，我们已经取得了一些发现，证明了一条新的 采用反向遗传学方法的调查。这些发现既有先天的，也有后天的 白足鼠种群的Nos 2基因的结构变异， 可以解释在感染过程中一氧化氮和活性氮的产生减弱。（二） Peromyscus中编码高亲和力IgG Fc受体蛋白的失活Fcgr 1基因的证据 (FcγR1或CD 64）。(3)MHCII类基因与 以及对伯氏疏螺旋体OspA蛋白的抗体应答。新目标包括四个子目标， 目的：（A）白足拟杆菌中Nos 2基因及其3 '-UTR的变体的宿主应答表型，（B）功能性 （C）在施用后，MHCII基因和针对OspA的抗体的变化， （D）高通量发现和注释在免疫中分离的结构变体。 殖民地这项由行政补充支持的新研究预计将有两个基本的 研究和转化研究及应用的影响。这些发现也可以指导临床研究， 莱姆病和其他蜱传感染患者的持续性疾病。