Modeling tuberculosis infection in a new collection of genetically diverse mice

在一组新的遗传多样性小鼠中建立结核感染模型

• 批准号: 9808825
• 负责人: Sarah A Stanley
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-10 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808825
• 关键词: Address; Antibiotics; Body Weight decreased; Cervical lymph node group; Cessation of life; Characteristics; Clinical; Collection; Communicable Diseases; Complex; Complex Genetic Trait; Development; Disease; Disease Outcome; Equilibrium; Future; Genetic; Genetic Determinism; Genetic Diseases; Genetic Heterogeneity; Genetic Variation; Genomics; Geography; Goals; Heterogeneity; Histopathology; House mice; Human; Human Genome; Hybrids; Immune; Immune response; Immunity; Immunologics; Inbred Mouse; Inbreeding; Individual; Infection; Infection Control; Laboratories; Link; Locales; Lung; Maps; Modeling; Mouse Strains; Mus; Mus musculus domesticus; Mycobacterium tuberculosis; Neuraxis; Outcome; Patients; Phenotype; Population; Predisposition; Quantitative Trait Loci; Reporting; Reproducibility of Results; Resistance; Resolution; Resources; Retinal blind spot; Risk; Site; Sterility; Techniques; Time; Tuberculosis; Vaccines; Variant; causal variant; combat; effective intervention; genome wide association study; human disease; improved; insight; mouse model; novel; novel therapeutics; pandemic disease; pathogen; pathogenic bacteria; response; tool; trait

Project Summary. Infection with Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis (TB), causes ~1.7 million deaths annually. The difficulty of treating Mtb infections with antibiotics and the lack of an effective vaccine fuel the TB pandemic. The development for effective interventions is impeded by the fact that we have very little understanding of the factors that underlie successful immune control of Mtb, or that dictate the heterogenous clinical manifestations observed in human patients. In this proposal we seek to establish that a newly derived collection of genetically diverse wild inbred mice is a powerful tool for dissecting the genetic basis of susceptibly to Mtb. The mouse model is a powerful tool for studying immune responses to Mtb. However, common laboratory strains have very limited genetic diversity. Two collections of mice, the collaborative cross and diversity outbred mice, were established to provide a genetically diverse set of mice that can be used to map the genetic basis of complex traits. Several recent studies have demonstrated the mice from these collections do have heterogenous responses to Mtb infection. Here we describe a new collection of wild-derived inbred mice, all from the Mus musculus domisticus subspecies, that offer several advantages over existing collections. This new collection of mice has the genetic diversity of natural populations, a lack of genomic “blind spots” created by crossing subspecies of mice, and linkage equilibrium that decays over a short genomic interval, facilitating the identification of causal genes. In this exploratory study we propose to infect 40 new lines of these wild-derived mice, and to assess their susceptibility to infection with Mtb using bacterial burden and weight loss studies. In addition, we will perform a preliminary immunological analysis of the most resistant and susceptible strains, to prioritize strains that may reveal new immunological mechanisms for future analysis. We will also attempt to identify strains that recapitulate aspects of human disease not seen in the current mouse models, including the ability to decrease bacterial burdens in the lungs over time, or dissemination to extrapulmonary sites such as the central nervous system. If successful, this study will establish that wild derived mice will be a valuable resource for uncovering novel mechanisms of immunity, and for modeling the heterogenous responses to infection with Mtb observed in humans.

项目摘要。结核分枝杆菌 (Mtb) 感染，该疾病的病原体 结核病 (TB) 每年导致约 170 万人死亡。用抗生素治疗结核分枝杆菌感染的困难 缺乏有效的疫苗加剧了结核病的流行。有效干预措施的发展是 由于我们对成功免疫的基础因素知之甚少，这一事实阻碍了我们 Mtb 的控制，或决定在人类患者中观察到的异质临床表现。在这个 我们寻求建立新衍生的遗传多样性野生近交小鼠集合的提案 剖析 Mtb 易感性遗传基础的有力工具。鼠标模型是一个强大的工具 研究对 Mtb 的免疫反应。然而，常见的实验室菌株的遗传多样性非常有限。 建立了两个小鼠集合，即协作杂交小鼠和多样性远交小鼠，以提供 一组具有遗传多样性的小鼠，可用于绘制复杂性状的遗传基础图谱。最近的几个 研究表明，这些收集的小鼠确实对结核分枝杆菌感染有异质反应。 在这里，我们描述了一组新的野生近交系小鼠，全部来自家家小家鼠 (Mus musculus domisticus) 亚种，与现有系列相比具有多种优势。这个新的小鼠系列具有 自然种群的遗传多样性，缺乏因杂交亚种而产生的基因组“盲点” 小鼠，以及在较短的基因组间隔内衰减的连锁平衡，有助于识别因果关系 基因。在这项探索性研究中，我们建议感染这些野生小鼠的 40 个新品系，并评估 通过细菌负荷和体重减轻研究，了解他们对 Mtb 感染的易感性。此外，我们将 对最具耐药性和易感性的菌株进行初步免疫学分析，以确定菌株的优先顺序 这可能会揭示新的免疫学机制以供未来分析。我们还将尝试识别菌株 概括了当前小鼠模型中未见的人类疾病的各个方面，包括能够 随着时间的推移，减少肺部的细菌负担，或传播到肺外部位，例如 中枢神经系统。如果成功，这项研究将证明野生小鼠将是有价值的 用于揭示新的免疫机制以及对异质反应进行建模的资源 在人类中观察到 Mtb 感染。