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，项目中添加了第四个具体目标：功能 自然发生的遗传变异对白鼠对伯氏疏螺旋体反应的影响。 父项目主要需要采用正向遗传学方法来识别性状并最终 描述白足鹿鼠作为主要储存库的能力的机制 多种人畜共患病原体，包括莱姆病的病因，同时在存在的情况下保持健康 在迄今为止的项目过程中，我们的发现证明了新系列的合理性。 采用反向遗传学方法的研究发现代表了先天性和后天性。 Peromyscus免疫中的免疫：（1）P. leucopus种群Nos2基因的结构变异 （2）可以解释感染期间一氧化氮和活性氮的产生减弱的原因。 Peromyscus 中存在编码高亲和力 IgG Fc 受体蛋白的失活 Fcgr1 基因的证据 巨噬细胞和其他吞噬细胞（FcγR1 或 CD64） (3) MHC II 类基因之间的关联。 以及针对伯氏疏螺旋体 OspA 蛋白的抗体反应 新目标包括四个亚组。 目的：(A) 白斑 P. leucopus 中 Nos2 基因及其 3'-UTR 变体的宿主反应表型，(B) 功能性 Peromyscus 突变体 Fcgr1 的影响，(C) MHC II 基因和 OspA 抗体的变异 免疫，以及（D）高通量发现和注释分离的结构变体 预计该行政补充支持的新研究将具有这两个基础。 研究和转化研究及应用影响。这些发现也可能指导临床研究。 莱姆病和其他蜱传感染患者的持续疾病。