Modeling tuberculosis infection in a new collection of genetically diverse mice

项目摘要。感染结核病的病原体--结核分枝杆菌(Mtb) 结核病每年造成约170万人死亡。用抗生素治疗结核分枝杆菌感染的难点 缺乏有效的疫苗助长了结核病的流行。有效干预措施的发展是 由于我们对免疫成功的基础因素知之甚少这一事实 控制结核分枝杆菌，或决定在人类患者中观察到的不同临床表现。在这 我们寻求建立一个新衍生的遗传多样性的野生近交系小鼠集合是一个 分析结核分枝杆菌易感性遗传基础的有力工具。鼠标模型是一种强大的工具 研究结核分枝杆菌的免疫反应。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，协作性杂交小鼠和多样性近交系小鼠，以提供 基因多样化的一组小鼠，可用于绘制复杂特征的遗传基础图。最近的几个 研究表明，这些收集的小鼠对结核分枝杆菌感染确实有不同的反应。 在这里，我们描述了一个新的野生近亲交配小鼠集合，这些小鼠都来自于小家鼠 亚种，这比现有的收藏提供了几个优势。这一新的老鼠集合拥有 自然种群的遗传多样性，缺乏通过杂交亚种造成的基因组“盲点” 小鼠，以及在短基因组间隔内衰退的连锁平衡，有助于确定病因 基因。在这项探索性研究中，我们提议感染40个新的野生来源小鼠品系，并评估 使用细菌负荷和体重减轻研究他们对结核分枝杆菌感染的敏感性。此外，我们还将 对最耐药和最敏感的菌株进行初步免疫学分析，以确定菌株的优先顺序 这可能会为未来的分析揭示新的免疫学机制。我们还将尝试鉴定菌株 这概括了人类疾病的一些方面，这在目前的小鼠模型中是没有的，包括 随着时间的推移，减少肺部的细菌负荷，或传播到肺外部位，如 中枢神经系统。如果成功，这项研究将确立野生来源的小鼠将是一种有价值的 用于发现新的免疫机制和对异种反应进行建模的资源 在人类中观察到结核分枝杆菌感染。

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.