ROLE OF INDUCIBLE BRONCHUS ASSOCIATED LYMPHOID TISSUE IN LATENT TUBERCULOSIS

 描述（由申请人提供）： 获得性免疫缺陷综合征（艾滋病）和结核病之间的全球性传染病相互作用具有致命的后果。在感染艾滋病毒的3860万人中，有三分之一同时感染结核分枝杆菌（Mtb），导致结核病成为艾滋病患者死亡的最大单一原因。然而，介导TB/HIV共感染宿主中Mtb控制丧失的机制尚不清楚。HIV诱导的CD 4 + T细胞下降与结核病易感性增加相关。此外，HIV诱导的CD 4 + T细胞耗竭也可能发生在肺肉芽肿内，损害Mtb控制，并促进从潜伏性TB（LTBI）进展为肺TB（PTB）。因此，尽管肉芽肿被认为对结核分枝杆菌控制很重要，但直到最近才描述了LTBI期间观察到的保护性肉芽肿与PTB期间观察到的非保护性肉芽肿之间的免疫学差异。我们最近在人、非人灵长类动物（NHP）和小鼠TB模型中的工作已经证明了诱导型支气管相关类风湿组织（iBALT）在TB中的作用。iBALT含有空间组织的T细胞、B细胞和巨噬细胞，其存在与TB期间更好的保护性结果相关。此外，我们新发表的数据表明，在PTB中，肉芽肿性炎症的主要特征是产生炎性分子如S100 A8/A9蛋白的中性粒细胞的积累。顺便说一句，增加的中性粒细胞积聚最近也与TB/HIV合并感染患者中增加的Mtb和病毒负荷相关。基于这些新的数据，我们提出了范式转移假说，即保护性TB肉芽肿是一种含有iBALT并有助于LTBI期间Mtb遏制的肉芽肿。相反，进展为更嗜酸性的炎性肉芽肿会导致TB再活化、Mtb控制丧失和进展为PTB。在本提案中，我们将通过三个具体目标来检验这一总体假设。在目标1中，使用TB的小鼠和NHP模型，我们将机械地鉴定调节iBALT形成的Mtb基因和途径，提供关于Mtb在干扰保护性iBALTs形成中所采用的机制的关键新信息。在目标2中，我们将讨论持续性iBALT在限制潜伏感染小鼠的再激活和传播中的功能作用。此外，我们还将讨论CD 4 + T细胞在iBALT中的相关性。 使用TB/SIV共感染的NHP模型的功能。在目标3中，我们将确定是否可以增强iBALT结构或逆转嗜酸性肉芽肿，以减少潜伏期和SIV合并感染期间的TB再活化和疾病严重程度。总之，这些目标将提供有关iBALT在潜伏期、TB再激活方面的临床相关性的新信息，并确定新型HDT以降低TB再激活率，特别是在HIV合并感染的情况下。毫无疑问，全球结核病负担的任何减少也将大大减少艾滋病毒-结核病综合症的致命后果。

 DESCRIPTION (provided by applicant): The global syndemic interaction between the acquired immunodeficiency syndrome (AIDS) and tuberculosis (TB) epidemics has deadly consequences. One third of the 38.6 million people infected with HIV are co-infected with Mycobacterium tuberculosis (Mtb), resulting in TB being the largest single cause of death in AIDS patients. However, the mechanism(s) that mediates loss of Mtb control in TB/HIV co- infected hosts are not known. HIV-induced decline in CD4+ T cells correlates with increased susceptibility to TB. In addition, HIV-induced CD4+ T cell depletion may also occur within the lung granuloma, impairing Mtb control, and facilitating progression from latent TB (LTBI) to Pulmonary TB (PTB). Thus, although the granuloma is considered important for Mtb control, the immunological differences between a protective granuloma seen during LTBI, and a non-protective granuloma seen during PTB have not been described until recently. Our recent work in human, Nonhuman primate (NHP) and mouse models of TB, has demonstrated a role for inducible Bronchus Associated Lymphoid tissue (iBALT) in TB. iBALT contains spatially organized T cells, B cells and macrophages and its presence is associated with better protective outcomes during TB. In addition, our new published data show that in PTB, a dominant feature of the granulomatous inflammation is the accumulation of neutrophils that produce inflammatory molecules such as S100A8/A9 proteins. Incidentally, increased neutrophil accumulation has also been recently associated with increased Mtb and viral burden in TB/HIV co-infected patients. Based on these new data, we propose the paradigm-shifting hypothesis that a protective TB granuloma is one that contains iBALT and contributes to Mtb containment during LTBI. In contrast, progression to a more neutrophilic, inflammatory granuloma causes TB reactivation, loss of Mtb control and progression to PTB. In this proposal, we will test this overall hypothesis through three specific Aims. In Aim 1, using mouse and NHP models of TB, we will mechanistically identify Mtb genes and pathways that modulate iBALT formation, providing crucial new information about the mechanism(s) employed by Mtb in interfering with the formation of protective iBALTs. In Aim 2, we will address the functional role of persistent iBALT in limiting reactivation and dissemination in latently infected mice. In addition, we will also address the relevance of CD4+ T cells in iBALT function using the NHP model of TB/SIV co-infection. In Aim 3, we will determine whether iBALT structures can be enhanced, or neutrophilic granulomas reversed, to decrease TB reactivation and disease severity during latency and SIV co-infection. Together, these aims will provide new information on the clinical relevance of iBALT in latency, reactivation of TB, and identify novel HDTs to decrease TB reactivation rates, particularly in a setting of HIV co-infection. Without doubt, any decrease in global TB burdens will also significantly decrease the deadly consequences of the HIV-TB syndemic.