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: 10265560
• 负责人: Alan G. Barbour
• 金额: $ 69.12万
• 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/10265560
• 关键词: ATAC-seq; Adult; Animals; Antibodies; Bacteria; Biological; Biological Models; Blood; Borrelia burgdorferi; Breeding; CRISPR gene drive; CRISPR/Cas technology; Candidate Disease Gene; Chiroptera; Chromatin; Chromosome Mapping; Chromosomes; Communities; Competence; Coupled; Data; Deer Mouse; Development; Diploidy; Disease; Disease Notification; Ebola virus; Enhancers; Equilibrium; Euthanasia; Female; Gene Targeting; Genes; Genetic; Genetic Crosses; Genetic Models; Genetic Structures; Genome; Genomic Segment; Genomics; Genotype; Goals; Growth; Haplotypes; High Prevalence; Human; Immune response; Immunity; Infection; Inflammation; Intervention; Knock-out; Larva; Life Cycle Stages; Linkage Disequilibrium; Lyme Disease; Mammals; Measurement; Measures; Mediating; Modeling; Molting; Muridae; Mus; North America; Nymph; Organ; Parasites; Pathology; Peromyscus; Persons; Phenotype; Population; Prevalence; Process; Resources; Rodent; Rodent Model; Role; SARS coronavirus; Sample Size; Skin; Tick-Borne Diseases; Ticks; Time; Tissues; Transgenic Model; Transgenic Organisms; United States; Variant; Vector-transmitted infectious disease; Wild Animals; animal colony; base; chronic infection; cohort; combat; experimental study; foot; forward genetics; genetic approach; genetic architecture; genome browser; genome wide association study; genome-wide; insight; inter-individual variation; interest; knockout gene; male; microbial; pathogen; primary endpoint; promoter; rate of change; secondary endpoint; success; tick transmission; tick-borne; trait; transmission process

Project Summary Lyme disease, one of the most commonly reported infectious diseases in North America, is caused by the tick-borne bacterium Borreliella burgdorferi. Although humans and other large mammals can be infected by B. burgdorferi, in order to complete its life-cycle in the wild the bacteria relies on rodent reservoirs, the major one being Peromyscus leucopus, the white-footed deermouse. The role of P. leucopus in Lyme disease and several other tick-borne diseases is analogous to that of bats as reservoirs for SARS coronaviruses and Ebola virus. In this proposal we continue the development of P. leucopus as an emerging genetic model system for the study of infectious and other diseases by maintaining and expanding genomic and biological resources for this species. These resources are the starting point for any gene-focused experiments in the Peromyscus genus. The primary goal of this proposal is to identify segregating genetic factors that impact the competence of P. leucopus as a reservoir of B. burgdorferi. The trait of reservoir competence is measured as the prevalence of infection and corresponding bacterial burdens among a cohort of nymphs that had molted from larvae previously fed on experimentally-infected deermice. Secondary endpoints include rates of growth and decline of the bacteria in the blood and skin of the animals and selected host responses, such as antibodies to the agent and inflammation of tissues, over the time course of the infection. It would normally be extremely difficult to carry-out large-scale genotyping and/or genetic crosses in an emerging rodent model. Here we show that our genome assembly for P. leucopus in concert with low pass short read sequences from a long-term closed colony of deermice can be leveraged to accurately impute SNP and haplotype genotypes on a genome- wide scale. These genotypes are then used to identify genes contributing to the remarkable capacity of P. leucopus to serve as a key reservoir host for B. burgdorferi and other disease agents. Finally, a subset of identified genes will be validated via CRISPR/Cas9 gene knock-outs in P. leucopus spearheaded by the person who pioneered transgenics for this genus. The identification of reservoir competence mediating genes may suggest better interventions to block transmission and provide insights into the management of human infections.

项目概要 莱姆病是北美最常见的传染病之一 由蜱传细菌伯氏疏螺旋体 (Borreliella burgdorferi) 引起。尽管人类和其他大型 哺乳动物可以被伯氏疏螺旋体感染，以在野外完成其生命周期 细菌依赖于啮齿动物宿主，其中主要的宿主是白足鼠（Peromyscus leucopus） 鹿鼠。 P. leucopus 在莱姆病和其他几种蜱传疾病中的作用是 类似于蝙蝠作为SARS冠状病毒和埃博拉病毒的宿主。在这个提案中 我们继续开发 P. leucopus 作为研究的新兴遗传模型系统 通过维持和扩展基因组和生物学来控制传染病和其他疾病 该物种的资源。这些资源是任何以基因为中心的研究的起点 Peromyscus 属的实验。该提案的主要目标是确定 分离影响 P. leucopus 作为 B. 博格多弗里。储存宿主能力的特征通过感染的流行率和 从幼虫蜕皮的一群若虫中相应的细菌负担 之前以实验感染的鹿鼠为食。次要终点包括 动物和选定宿主的血液和皮肤中细菌的生长和衰退 随着时间的推移，反应，例如针对药剂的抗体和组织炎症 感染。进行大规模基因分型和/或 新兴啮齿动物模型中的遗传杂交。在这里，我们展示了 P. 的基因组组装。 leucopus 与来自长期封闭菌落的低通短读序列相配合 deermice 可用于准确地估算基因组上的 SNP 和单倍型基因型 规模大。然后使用这些基因型来识别导致显着的基因 P. leucopus 作为伯氏疏螺旋体和其他疾病的关键储存宿主的能力 代理。最后，将通过 CRISPR/Cas9 基因敲除来验证已识别基因的子集 在P. leucopus 中，由该属的转基因先驱者带头。这 识别储库能力介导基因可能会建议更好的干预措施 阻止传播并为人类感染的管理提供见解。