The Effects of M. tuberculosisInfection on Lung Microbiome in Macaques

 描述(申请人提供)：结核病仍然是全球发病率和死亡率的主要原因。尽管进行了多年的研究，但我们对人类宿主和结核分枝杆菌之间复杂相互作用的理解仍然不完整。特别是，在细菌和宿主之间感染早期发生的事件被了解得非常少，主要是因为它们在临床上是沉默的。然而，我们在非人类灵长类结核病模型中的数据表明，早期事件是感染最终结果的关键和预测。最近的研究表明，人类微生物群在影响和塑造免疫反应和宿主对感染的结果方面发挥着关键作用，以及在肥胖、心脏病和COPD等其他疾病中发挥作用。虽然大多数研究都集中在肠道微生物组上，但最近肺微生物组一直是一个丰富的研究领域。到目前为止，关于结核分枝杆菌感染和肺部微生物群之间是否存在显著相互作用的数据很少。在这项提案中，我们将使用一个非人类灵长类结核分枝杆菌感染模型，该模型忠实地概括了人类结核病的各个方面，以调查结核分枝杆菌感染对肺部微生物群的影响。该项目将彻底评估这种感染是否会改变猕猴的肺部微生物群，包括改变的幅度和持续时间。我们将首先收集感染前和感染期间的连续呼吸道样本，然后对这些样本的微生物组进行测序和分析，以解决这些问题。使用PET/CT成像技术评估感染的连续进展，我们将把微生物群变化的幅度和持续时间与肺部炎症联系起来。该项目将提供一个独特的机会，开始研究肺微生物群和结核分枝杆菌之间的动态关系，并将为未来评估肺微生物群对结核分枝杆菌感染的敏感性、免疫反应和感染结果的重要性的研究奠定框架。该项目代表了复制人类结核病模型的结核病研究的新方向，是拥有结核病猕猴模型专业知识的实验室和具有肺微生物组分类特征专业知识的实验室之间的合作。

 DESCRIPTION (provided by applicant): Tuberculosis remains a major cause of morbidity and mortality worldwide. Despite years of research, our understanding of the complex interactions between the human host and Mycobacterium tuberculosis remains incomplete. In particular, the events that occur early in infection between the bacteria and the host are very poorly understood, primarily due to their clinically silent nature. However, our data in a non-human primate model of tuberculosis point to early events as crucial and predictive of eventual outcome of infection. Recent studies have implicated the human microbiome as playing a pivotal role in influencing and shaping the immune response and host outcome to infections, as well as in other diseases including obesity, heart disease, and COPD. Although most studies have focused on the gut microbiome, more recently the lung microbiome has been a rich area for research. To date, there is little data on whether there is significant interaction between M. tuberculosis infection and the lung microbiome. In this proposal, we will use a non-human primate model of M. tuberculosis infection, which faithfully recapitulates all aspects of human tuberculosis, to survey the changes that M. tuberculosis infection elicits upon the lung microbiome. This project will provide a thorough assessment of whether this infection alters the lung microbiome in macaques, including the magnitude and duration of change. We will initially collect serial airway samples prior to and throughout infection and subsequently sequence and analyze the microbiome of these samples to address these questions. Using PET/CT imaging technologies to assess serial progression of the infection, we will correlate magnitude and duration of change in the microbiome to inflammation within the lungs. This project will provide a unique opportunity to begin to tackle the dynamics between the lung microbiome and M. tuberculosis and will lay the framework for future studies to assess the importance of the lung microbiome to susceptibility, immune responses and infection outcome in M. tuberculosis infection. This project represents a new direction for TB research in a model that replicates human TB, and is a collaboration among labs with expertise in the macaque model of TB and those with expertise in taxonomic characterization of the lung microbiome.