Predicting immune responses that correlate with protection against tuberculosis

描述(申请人提供)：结核病每年造成200万人死亡。即使经过几十年的研究，我们对预防人类结核病的机制的理解仍然存在许多空白。在这项建议中，我们采取了一种独特的多管齐下的系统生物学方法，结合了接近模拟人类结核杆菌感染的所有方面的非人类灵长类动物感染模型，与仅部分有效的疫苗(导致受保护和非受保护动物)，以及最先进的活体动物成像、免疫监测和计算模型，以识别和预测对结核病具有保护作用的免疫机制。这项提议将开发一个多学科的“工具箱”，用于解剖人类免疫反应，提供对细菌感染的保护，甚至超过结核病。我们在结核病的计算模拟方面积累了大量经验，并将首次生成具有多尺度相互作用(分子到细胞到器官到宿主尺度)的血液、肺、淋巴的3个生理室模型，纳入该项目中从非人类灵长类动物产生的数据，以及我们之前的数据和文献中的数据。这些模型将被用来识别保护的代理标记，这些标记将被用来预测受这种疫苗保护的动物。反过来，实验动物将成为肉芽肿和淋巴组织的来源，以探索感染部位的实际保护反应，这是不可能在人类身上完成的研究。通过计算模型和实验模型之间的迭代，我们将确定共同有助于保护性免疫反应的因素。这些研究对于更详细地了解宿主对结核病的免疫反应以及开发和测试预防这种疾病的新的治疗和干预策略是必要的一步。

DESCRIPTION (provided by applicant): Tuberculosis is responsible for 2 million deaths every year. Even after decades of research, there are still numerous gaps in our understanding of the mechanisms that provide protection against tuberculosis in humans. In this proposal, we take a unique multipronged systems biology approach, combining a non-human primate model of M. tuberculosis infection that closely mimics all aspects of human M. tuberculosis infection, with a vaccine that is only partially effective (resulting in protected and non-protected animals), and state-of- the-art live animal imaging, immunologic monitoring, and computational models, to identify and predict the immunologic mechanisms that are protective against TB. This proposal will develop a multi-disciplinary "tool- box" for dissecting human immune responses that provide protection against bacterial infections, even beyond TB. We build on considerable experience in computational modeling of tuberculosis and will generate a first- time 3 physiologic compartment model of blood, lung, lymph node with multi-scale interactions (molecular to cellular to organ to host scales), incorporating data generated in this project from the non-human primate, as well as our previous data and that from the literature. These models will be used to identify surrogate markers of protection, which will be used to predict the animals that are protected by this vaccine. In turn, the experimental animals will be the source of granuloma and lymph node tissue to probe the actual protective responses at the site of infection, studies that are impossible to do in humans. Through iteration between computational and experimental models, we will identify the factors that together can contribute to a protective immune response. These studies are a necessary step to a more detailed understanding of host immune responses protective against tuberculosis, and development and testing of new therapeutic and intervention strategies to prevent this disease.