Pulmonary Innate Immunity & Resistance to Mycobacterium Tuberculosis Infection

尽管100多年前发现了结核分枝杆菌(Mtb)，而且有了 60多年来的有效药物，控制结核病(TB)疾病仍然存在巨大的障碍 包括缺乏高效疫苗，长期的药物治疗方案，预防感染，以及 杀死巨噬细胞内的休眠细菌。在与肺结核患者密切接触后，大多数人 出现潜伏的结核分枝杆菌感染(LTBI)。然而，有些人天生就对感染具有抵抗力(RSTR)。 耐药机制尚不清楚，可能为新的治疗策略提供洞察力。在一个 过去20年在乌干达城市进行的大规模结核病家庭接触研究发现，~9%的密切成年人 家庭接触者TST和干扰素-伽马释放试验(IGRA)持续呈阴性 延长了随访时间。据我们所知，这个庞大的乌干达队列是独一无二的，具有严格的纵向临床 和流行病学数据。利用全基因组图谱从结核分枝杆菌感染的外周血中分离出mRNA- 来源的单核细胞，我们比较了RSTR和LTBI组的转录特征。我们发现， 组蛋白脱乙酰酶(HDAC)基因家族区分RSTR和LTBI，并可能调节对Mtb的抗性 感染。HDAC调节转录，一些家族成员介导先天免疫反应 微生物。我们还发现HDAC1基因的多态与抵抗感染有关。在……里面 HDAC抑制剂治疗外周血单核细胞和肺泡巨噬细胞减少结核分枝杆菌 与未经处理的细胞相比进行复制。这些发现支持了RSTR具有保护作用的概念 依赖单核细胞的先天免疫反应。然而，有几个关键问题需要 包括阐明HDAC介导的结核分枝杆菌控制的分子和遗传机制 巨噬细胞的复制与临床对结核分枝杆菌感染的耐药性。此外，肺泡的作用 巨噬细胞在调节HDAC介导的免疫反应中的作用还知之甚少。我们假设 HDAC通过转录调控抗结核分枝杆菌抗体抑制结核分枝杆菌复制来介导对感染的抵抗力 微生物途径。HDAC依赖的免疫反应的特征将使识别 对结核分枝杆菌感染的天然抵抗机制。后者将为我们提供新的视角来理解 结核病发病机制，指出结核病疫苗和药物开发的新方法，并确定 抵抗和/或清除结核分枝杆菌感染。研究目标将与指导战略相结合 对于辅导者来说，这促进了以患者为导向的研究的发展，为他们提供了一条独立的途径。

Despite the discovery of Mycobacterium tuberculosis (Mtb) over 100 years ago and the availability of effective drugs for over 60 years, there remain formidable hurdles for controlling tuberculosis (TB) disease including the lack of a highly efficacious vaccine, long drug treatment regimens, prevention of infection, and killing dormant bacilli within macrophages. After close contact with a person with pulmonary TB, most people develop latent Mtb infection (LTBI). However, some individuals are naturally resistant to infection (RSTRs). The mechanisms of resistance are unknown and may provide insight into novel therapeutic strategies. In a large TB household contact study in urban Uganda over the past 20 years, we found that ~9% of close adult household contacts remained persistently TST and Interferon-gamma Release Assay (IGRA) negative during extended follow-up. To our knowledge, this large Ugandan cohort is unique with rigorous longitudinal clinical and epidemiologic data. Using genome-wide profiling of mRNA isolated from Mtb-infected peripheral blood- derived monocytes, we compared transcriptional signatures in the RSTR and LTBI groups. We found that the histone deacetylase (HDAC) gene family distinguishes RSTRs from LTBIs and may regulate resistance to Mtb infection. HDACs regulate transcription and some family members mediate the innate immune response to microbes. We also found polymorphisms in HDAC1 that are associated with resistance to infection. In peripheral blood monocyte-derived and alveolar macrophages, HDAC inhibitor treatment decreased Mtb replication in comparison to untreated cells. These findings support the concept that RSTRs have protective innate immune responses that are monocyte-dependent. However, several critical questions need to be addressed including elucidation of the molecular and genetic mechanisms of HDAC-mediated control of Mtb replication in macrophages and clinical resistance to Mtb infection. In addition, the role of alveolar macrophages in regulating HDAC-mediated immune responses is poorly understood. We hypothesize that HDACs mediate resistance to infection by inhibiting Mtb replication through transcriptional regulation of anti- microbial pathways. Characterization of HDAC-dependent immune responses will enable identification of natural resistance mechanisms to Mtb infection. The latter will provide new insight into our understanding of TB pathogenesis, point to novel approaches to TB vaccine and drug development, and identify biomarkers of resistance to and/or clearance of Mtb infection. The research aims will be integrated with a mentoring strategy for mentees that fosters development of patient-oriented research with a pathway to independence.