Role of Inducible Bronchus Associated Lymphoid Tissue in Latent Tuberculosis

项目摘要/摘要 世界上大约四分之一的人口潜伏感染结核分枝杆菌 (MTB)和感染者一生中患临床型肺结核(PTB)的风险为10% 一辈子。全球抗击结核病的努力因广泛耐药和多药耐药的出现而受阻 耐药菌株和目前可用的牛分枝杆菌卡介苗的可变效力。 不幸的是，控制从LTBI到PTB进展的免疫机制并不明确，从而阻止了 合理设计促进结核病免疫控制的治疗方法或疫苗。因此，迫切需要 更好地了解有助于控制结核分枝杆菌的免疫参数。结节肉芽肿是一个标志 这对结核病的免疫控制很重要。然而，并不是所有的肉芽肿都能有效控制。 结核病，因为它们在长期脑损伤期间以及在结核再激活(TB-R)和肺结核期间都可以看到。在之前的R01中 在资助期间，我们使用了人类结核病样本以及非人类灵长类动物(NHP)和小鼠结核病模型来 展示对诱导性支气管相关淋巴组织(IBALT)的明确保护作用 在对结核分枝杆菌感染的初级和疫苗诱导反应期间，包含明确定义的B细胞毛囊。 此外，我们确定了肺结核期间肉芽肿的一个主要特征是中性粒细胞的聚集。 产生促炎分子，如S100A8/A9蛋白，并限制iBALT的形成。我们的长期合作 目标是制定临床策略，以抑制结核分枝杆菌的生长，防止从LTBI到结核病的进展。 基于R01资助的工作，R01更新的目标是确定肉芽肿的角色- 相关B细胞和中性粒细胞在结核病感染和疾病进展中的作用以及确定iBALT是否是一种 预防结核病进展的有效目标。为了实现这一总体目标，我们建议使用两种小动物 和大型动物模型来解决以下具体目标：在具体目标1中，我们将调查 IBALT驻留的B细胞在预防结核病中的作用；在特定的目标2中，我们将评估中性粒细胞的作用 S100A8/A9等蛋白在PTB中限制iBALT的作用，并确定是否靶向S100A8/A9通路 将减少结核病和改善结核控制；最后，在具体目标3中，我们将确定iBALT结构 可用于预防结核分枝杆菌感染宿主中的结核病进展。从这些研究中获得的知识 具有重大意义，因为它将直接推动新疗法和疫苗战略的发展，以限制 TB-R和进展为结核病。

PROJECT SUMMARY/ABSTRACT Approximately one-fourth of the world's population is latently infected (LTBI) with Mycobacterium tuberculosis (Mtb) and those infected have a 10% lifetime risk of developing clinical pulmonary TB (PTB) disease over their lifetime. Global efforts to combat TB are hampered by the emergence of extensively drug-resistant and multidrug- resistant strains and the variable efficacy of the currently available vaccine, M. bovis Bacille Calmette Guerin. Unfortunately, the immune mechanisms that govern progression from LTBI to PTB are poorly defined, preventing rational design of treatments or vaccines that stimulate immune control of TB. Thus, there is an urgent need to better understand the immune parameters that contribute to Mtb control. The tubercle granuloma is a hallmark of TB and is important for the immune control of Mtb infection. However, not all granulomas effectively control TB, as they are seen both during LTBI and during TB reactivation (TB-R) and PTB. During the previous R01 funding period, we used human TB samples and non-human primate (NHP) and mouse models of TB to demonstrate an unequivocal protective role for inducible bronchus-associated lymphoid tissue (iBALT) containing clearly defined B-cell follicles during both primary and vaccine-induced responses to Mtb infection. Additionally, we determined that a dominant feature of granulomas during PTB is the accumulation of neutrophils that produce proinflammatory molecules such as S100A8/A9 proteins and limit iBALT formation. Our long-term goal is to develop clinical strategies to restrain Mtb growth and prevent progression from LTBI to TB disease. Based on work from this funded R01, the objective of this R01 renewal is to identify the roles of granuloma- associated B cells and neutrophils in TB infection and disease progression and to determine if iBALT is an effective target for preventing TB progression. Towards this overall goal, we propose to use both small animal and large animal models to address the following specific aims: In Specific Aim 1 we will investigate the role of iBALT-residing B cells in protecting against TB; In Specific Aim 2, we will evaluate the role of neutrophilic proteins such as S100A8/A9 in limiting iBALT during PTB, and to determine if targeting S100A8/A9 pathways will reduce TB disease and improve Mtb control; Finally, in Specific Aim 3, we will determine if iBALT structures can be targeted to prevent TB progression in Mtb-infected hosts. The knowledge to be gained from these studies is significant, as it will directly advance the development of new therapeutics and vaccine strategies for limiting TB-R and progression to TB.