Modeling tuberculosis infection in a new collection of genetically diverse mice

项目摘要。感染结核分枝杆菌（Mtb），这是疾病的病原体 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 以及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 我们对成功免疫的基础因素知之甚少， Mtb的控制，或决定在人类患者中观察到的异质性临床表现。在这 我们试图建立一个新的遗传多样性野生近交系小鼠的集合， 是剖析结核分枝杆菌遗传基础的有力工具。小鼠模型是一个强大的工具， 研究对结核杆菌的免疫反应然而，普通实验室菌株的遗传多样性非常有限。 建立了两个小鼠集合，协作杂交小鼠和多样性远交小鼠，以提供一种新的小鼠模型。 遗传多样性的小鼠，可用于绘制复杂性状的遗传基础。最近的几 研究已经证明来自这些收集的小鼠确实对Mtb感染具有异质性应答。 在这里，我们描述了一个新的收集野生衍生的近交系小鼠，所有从家鼠 亚种，提供了几个优势，比现有的收藏。这批新的老鼠 自然种群的遗传多样性，缺乏由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减的连锁平衡，有助于确定因果关系。 基因.在这项探索性研究中，我们建议感染40个新品系的这些野生小鼠，并评估 使用细菌负荷和体重减轻的研究，他们对结核分枝杆菌感染的易感性。此外，我们将 对最耐药和最敏感的菌株进行初步免疫学分析， 这可能揭示新的免疫机制，供未来分析。我们还将尝试识别菌株 这概括了在目前的小鼠模型中没有看到的人类疾病的方面，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，这项研究将建立野生小鼠将是一个有价值的， 资源，用于揭示免疫的新机制，并为模拟异质性反应， 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.