Role of Inducible Bronchus Associated Lymphoid Tissue in Latent Tuberculosis

诱导支气管相关淋巴组织在潜伏性结核病中的作用

• 批准号: 10352462
• 负责人: Deepak Kaushal
• 金额: $ 136.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2022-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352462
• 关键词: Address; Advanced Development; Animal Model; Animals; Antibody Response; Antigen Presentation; B-Lymphocyte Subsets; B-Lymphocytes; BCG Live; Bronchus-Associated Lymphoid Tissue; Cells; Cessation of life; Chronic; Clinical; Coin; Disease; Disease Progression; Drug resistance; Funding; Goals; Granuloma; Growth; Human; ITGAM gene; Immune; Immunologics; Integrins; Interleukin-6; Intervention; Knowledge; Lung; Lymphoid Follicle; Mediating; Modeling; Mucous Membrane; Multi-Drug Resistance; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Pathway interactions; Population; Predisposition; Proteins; Pulmonary Tuberculosis; Regulation; Resistance; Role; S100A8 gene; Sampling; Side; Signal Transduction; Structure; Structure of germinal center of lymph node; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccines; Work; base; chemotherapy; combat; design; experimental study; extensive drug resistance; immune activation; improved; inhibitor; lifetime risk; mouse model; nanoemulsion; neutrophil; nonhuman primate; novel; novel strategies; novel therapeutics; novel vaccines; prevent; rational design; receptor; resistant strain; small molecule inhibitor; therapy design; tuberculosis treatment; vaccine access; vaccine response; vaccine strategy

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.

项目总结/摘要 大约四分之一的世界人口是潜伏感染（LTBI）结核分枝杆菌 (Mtb)感染者在其一生中有10%的风险发展为临床肺结核（PTB）疾病。 辈子广泛耐药和多药结核病的出现阻碍了全球抗击结核病的努力- 耐药菌株和现有疫苗的可变效力，M.牛卡介苗 不幸的是，控制从LTBI进展到PTB的免疫机制定义不清， 合理设计刺激结核病免疫控制的治疗或疫苗。因此，迫切需要 更好地了解有助于结核分枝杆菌控制的免疫参数。结节肉芽肿是一个标志性的 结核病和重要的Mtb感染的免疫控制。然而，并非所有的肉芽肿都能有效地控制 TB，如在LTBI和TB再激活（TB-R）和PTB期间所见。在之前的R 01期间 在资助期间，我们使用人类结核病样本和非人灵长类动物（NHP）和小鼠结核病模型， 证明对诱导型支气管相关淋巴组织（iBALT）具有明确的保护作用 在对Mtb感染的初次和疫苗诱导的应答期间，含有明确定义的B细胞滤泡。 此外，我们确定PTB期间肉芽肿的一个主要特征是中性粒细胞的积聚 其产生促炎分子如S100 A8/A9蛋白并限制iBALT形成。我们的长期 目标是开发临床策略以抑制结核分枝杆菌生长并防止从LTBI发展为TB疾病。 基于该资助的R 01的工作，该R 01更新的目的是确定肉芽肿的作用- 相关的B细胞和中性粒细胞在TB感染和疾病进展中的作用，并确定iBALT是否是 预防结核病进展的有效靶点。为达致这个整体目标，我们建议使用小型动物， 和大型动物模型，以解决以下具体目标：在具体目标1中，我们将研究的作用， iBALT驻留的B细胞在预防TB中的作用;在具体目标2中，我们将评估嗜酸性粒细胞的作用。 蛋白质如S100 A8/A9在PTB期间限制iBALT，并确定靶向S100 A8/A9通路是否 最后，在具体目标3中，我们将确定iBALT结构是否 可以靶向预防结核病在结核分枝杆菌感染宿主中的进展。从这些研究中获得的知识 这是重要的，因为它将直接推动新疗法和疫苗策略的发展， TB-R和进展为TB。