COMMON IMMUNE CORRELATES OF RISK OF TB DISEASE IN ANIMAL MODELS AND HUMANS

 描述(申请人提供)：结核分枝杆菌(Mtb)感染了世界上约三分之一的人口，每年导致全世界约130万人死亡。虽然大多数感染者都是无症状感染者，但潜伏性结核病(LTBI)可以重新激活为肺结核(PTB)。清楚地了解结核病期间与疾病进展和炎症风险相关的免疫关系，对于设计新的免疫疗法和治疗以促进结核分枝杆菌控制是必要的。动物模型，如近亲交配的小鼠结核病模型，通常用于研究结核病的免疫或炎症机制。然而，在近交系小鼠模型中看到的疾病结果并不反映在人类结核病中看到的异质性。因此，我们建立了一个多样性杂交(DO)小鼠的结核病小鼠模型，这些小鼠在结核分枝杆菌感染后的疾病严重程度上表现出相当大的异质性。此外，非人类灵长类(NHP)结核病动物模型是研究结核病疾病进展的临床前模型，其中肉芽肿反映了人类结核病观察到的形态和生理。因此，利用结核的DO Mtb小鼠模型、NHP结核模型和人类临床样本，我们最近发现中性粒细胞和S100A8/A9蛋白在介导结核的炎症和疾病严重程度中起作用。然而，如果我们更全面地了解相关动物模型和人类结核病谱系中保护和炎症的共同免疫相关性，这种翻译发现的步伐将更加强劲和迅速。为了克服这一瓶颈，我们提出了以下目标。在目标1中，我们将从DO Mtb感染小鼠的外周血液和肺样本中识别共同的基因表达特征，并将它们与已有的SA青少年纵向研究中的全血转录谱进行比较。此外，我们将通过测量我们的青少年进步者队列中的蛋白质水平来验证从物种间基因表达分析中识别出的基因的表达。在目标2中，使用结核分枝杆菌感染的动物模型，我们将机械地解决特定基因在人类进展中被识别为与结核病风险相关的功能作用，特别是关注I型干扰素途径。总之，这些目标将提供有关相关动物模型和人类结核病之间存在的常见免疫保护和炎症途径的新信息。识别这些共同的相关性将使我们能够更有效地利用动物模型来筛选新的疫苗和疗法，这些疫苗和疗法更有可能转化为改善人类结核病的疗效。

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) infects about one third of the world's population, killing ~1.3 million individuals worldwide every year. Although, te majority of infected persons are asymptomatically infected, latent tuberculosis (LTBI) can reactivate into pulmonary tuberculosis (PTB). A clear understanding of immune correlates associated with risk of disease progression and inflammation during TB is necessary for design of new immunotherapies and treatments to promote control of Mtb. Animal models such as the inbred mouse model of TB are commonly used to study mechanisms of immunity or inflammation in TB. However, disease outcomes seen in inbred mouse models do not reflect the heterogeneity seen in human TB. Thus, we established a mouse model of TB in diversity outbred (DO) mice that demonstrate considerable heterogeneity in disease severity following Mtb infection. In addition, non-human primate (NHP) animal model of TB is a pre-clinical model for studying TB disease progression, where granulomas mirror the morphology and physiology observed in human TB. Thus, using the DO Mtb mouse model, NHP model of TB and human clinical samples, we recently implicated neutrophils and S100A8/A9 proteins in mediating inflammation and disease severity in TB. However, the pace of such translational discoveries will be much more robust and rapid if we have a more comprehensive understanding of common immune correlates of protection and inflammation across relevant animal models and the spectrum of TB in humans. To overcome this bottleneck, we propose the following Aims. In Aim 1, we will identify common gene expression signatures from peripheral blood and lung samples from DO Mtb-infected mice, NHPs with PTB and LTBI, and compare them to existing whole blood transcriptional profiles from a well characterized longitudinal study of SA adolescents. In addition, we will validate the expression of genes identified from the inter-species gene expression analysis by measuring protein levels in our human adolescent progressor cohort. In Aim 2, using animal models of Mtb infection, we will mechanistically address the functional role of specific genes identified as correlates of risk of TB in human progressors, specifically focusing on the Type I Interferon pathway. Together, these aims will provide novel information on common immune protective and inflammatory pathways that exist between relevant animal models and human TB. Identifying such common correlates will allow us to more effectively use animal models to screen for new vaccines and therapies that have a better likelihood of translating to improved efficacy in human TB.