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症(艾滋病)和结核病(结核病)流行之间的全球共同作用具有致命的后果。在感染艾滋病毒的3860万人中，有三分之一是合并感染结核分枝杆菌，导致结核病成为艾滋病患者的最大单一死因。然而，在结核/艾滋病毒混合感染的宿主中，介导结核分枝杆菌控制丧失的机制(S)尚不清楚。HIV引起的CD4+T细胞的下降与结核病易感性的增加有关。此外，HIV诱导的CD4+T细胞耗尽也可能发生在肺肉芽肿内，损害结核分枝杆菌的控制，并促进从潜伏性结核病(LTBI)向肺结核病(PTB)的进展。因此，尽管肉芽肿被认为对结核分枝杆菌的控制很重要，但LTBI期间出现的保护性肉芽肿和PTB期间出现的非保护性肉芽肿之间的免疫学差异直到最近才被描述出来。我们最近在人类、非人灵长类动物(NHP)和小鼠的结核病模型中的工作，证明了诱导性支气管炎相关淋巴组织(IBALT)在结核病中的作用。IBALT包含空间有序的T细胞、B细胞和巨噬细胞，它的存在与结核病期间更好的保护结果有关。此外，我们新发表的数据显示，在肺结核中，肉芽肿炎症的一个主要特征是中性粒细胞的聚集，这些中性粒细胞产生炎症分子，如S100A8/A9蛋白。顺便说一句，最近中性粒细胞堆积的增加也与结核分枝杆菌感染和艾滋病毒混合感染患者的病毒负担增加有关。基于这些新数据，我们提出了范式转换假设，即保护性结核肉芽肿是一种含有iBALT并有助于在LTBI期间遏制结核分枝杆菌的肉芽肿。相反，进展到更中性的炎性肉芽肿会导致结核病重新激活，失去对结核分枝杆菌的控制，并进展为肺结核。在这项提案中，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，利用小鼠和NHP结核模型，我们将机械地鉴定Mtb基因和调节iBALT形成的途径，提供关于Mtb干扰保护性iBALT形成的机制的关键新信息(S)。在目标2中，我们将讨论持久性iBALT在限制潜伏感染小鼠的重新激活和传播方面的功能作用。此外，我们还将讨论iBALT中CD4+T细胞的相关性 使用结核病/SIV混合感染的NHP模型。在目标3中，我们将确定是否可以增强iBALT结构或逆转中性粒细胞肉芽肿，以降低潜伏期和SIV合并感染期间结核病的重新激活和疾病严重程度。总之，这些目标将提供有关iBALT在结核病潜伏期和重新激活方面的临床相关性的新信息，并确定新的HDT以降低结核病重新激活率，特别是在艾滋病毒合并感染的情况下。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-结核病综合征的致命后果。

 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.