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.

项目摘要 莱姆病是北美最常见的传染病之一，是 由tick传播的细菌Borreliella burgdorferi引起。虽然人类和其他大 哺乳动物可以被B. burgdorferi感染，以便在野外完成生命周期 细菌依靠啮齿动物的储层，主要的储层是白色脚的peromyscus leucopus Deermouse。白假单胞菌在莱姆病和其他几种tick传播疾病中的作用是 类似于蝙蝠作为SARS冠状病毒和埃博拉病毒的储层。在此提案中 我们继续开发白菜假单胞菌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传染和其他疾病 该物种的资源。这些资源是任何以基因为中心的起点 Peromyscus属的实验。该提议的主要目标是确定 隔离遗传因素，影响白假单胞菌作为B的能力。 伯格多尔里。储层能力的特征被衡量为感染的流行率和 来自幼虫的若虫队中的相应细菌负担 先前在实验感染的Deermice上喂养。次要终点包括 细菌在动物的血液和皮肤中的生长和下降 反应，例如对组织的抗体和组织炎症的抗体， 感染。通常很难进行大规模的基因分型和/或 遗传杂交在新兴的啮齿动物模型中。在这里，我们证明了我们的基因组组件。 与低通读序列的蓝牙条与长期闭合菌落的伴奏 可以将Deermice杠杆化以准确地将SNP和单倍型基因型算在基因组上 大规模。然后，这些基因型用于识别有助于显着的基因 白菜假单胞菌作为B. b. b. b. b. b. b. b. b. b. b.b。 代理商。最后，将通过CRISPR/CAS9基因敲除验证的一部分确定基因 在leucopus率领的，由率先为该属的转基因的人带头。这 识别介导基因的储层能力可能会提出更好的干预措施 阻止传播并洞悉人类感染的管理。