Natural Resistance to Mycobacterium Tuberculosis Infection

 描述（由申请人提供）：结核病（TB）是全球主要的公共卫生负担。在与肺结核患者密切接触后，大多数人通过吸入雾化的结核分枝杆菌（MTB）而感染。大多数人控制这种感染而不消除它，并发展潜伏性MTB感染（LTBI），如通过阳性结核菌素皮肤试验（TST）和/或干扰素释放试验（IGRA）所测量的。在乌干达城市进行的一项大型结核病家庭接触研究中，我们惊讶地发现，9.1%的密切成年家庭接触者（HHC）在两年的随访期间持续保持TST阴性。持续的TST阴性状态表明一些个体可能抵抗和/或快速中止MTB感染。抗MTB感染（RSTR）的人的免疫反应的表征将使识别天然耐药机制MTB。RSTR的流行病学风险特征与患有或发展为LTBI的HHC没有显著差异。使用微阵列和从MTB感染的血液来源的单核细胞中分离的mRNA，我们确定了区分RSTR和LTBI患者的转录特征。具体而言，使用基因集富集分析和线性神经网络分析，我们发现伊马替尼-ABL途径和COLEC 10基因可以区分RSTR和LTBI，因此直接参与MTB感染或标记MTB感染的抗性。使用全基因组连锁研究，我们还发现了先天免疫途径中的基因变异，这些基因变异将RSTR与LTBI患者区分开来。这些结果支持该ICIDR的假设，即RSTR具有由巨噬细胞介导的保护性先天免疫应答。这一假设将在3个目标中进行检验。目标1.确定RSTR表型的长期稳定性并鉴定精英RSTR。确定全血MTB杀伤是否区分RSTR与LTBI个体。目标2。确定候选耐药基因ABL和COLEC 10如何调节来自RSTR和LTBI个体的巨噬细胞对MTB感染的反应的机制。目标3。确定肺泡巨噬细胞中ABL和COLEC 10功能以及MTB诱导的转录特征，这些转录特征与MTB感染的易感性或耐药性相关，并验证RSTR新队列中的发现。为了实现这一ICIDR的目标，我们汇集了一个多学科和经验丰富的长期合作研究人员在马凯雷雷大学（马扬贾，穆佩雷）在坎帕拉（乌干达），大学的华盛顿（霍恩，Seshadri）和凯斯西储大学（繁荣，约翰逊，斯坦）。该ICIDR项目将提供临床和实验室结核病研究方面的能力建设和培训机会。

 DESCRIPTION (provided by applicant): Tuberculosis (TB) is a major public health burden globally. After close contact with a person with pulmonary TB, most people become infected by inhaling aerosolized Mycobacterium tuberculosis (MTB). Most control this infection without eliminating it and develop latent MTB infection (LTBI) as measured by a positive tuberculin skin test (TST) and/or interferon- release assay (IGRA). In a large TB household contact study in urban Uganda we were surprised to find that 9.1% of close adult household contacts (HHC) remained persistently TST negative during two years of follow-up. The persistently TST negative state suggests that some individuals may either resist and/or rapidly abort MTB infection. Characterization of immune responses in persons resisting MTB infection (RSTR) will enable identification of natural resistance mechanisms to MTB. The epidemiological risk profiles of RSTRs did not differ significantly from HHC who had or developed LTBI. Using microarrays and mRNA isolated from MTB-infected blood-derived monocytes, we identified transcriptional signatures that distinguish RSTR from persons with LTBI. Specifically, using Gene Set Enrichment Analysis and Linear Neural Network analysis, we found that the imatinib-ABL pathway and the COLEC10 gene may distinguishes RSTR from LTBI and thus are either directly involved in or markers of resistance to MTB infection. Using a genome-wide linkage study, we also discovered gene variants in innate immune pathways that distinguished RSTR from persons with LTBI. These result support the hypothesis for this ICIDR that RSTR have protective innate immune responses that are mediated by macrophages. This hypothesis will be tested in 3 aims. Aim1. Determine the long-term stability of the RSTR phenotype and identify elite RSTRs. Determine whether whole blood MTB killing differentiates RSTRs from LTBI individuals. Aim2. Determine the mechanism of how the candidate resistance genes ABL and COLEC10 regulate responses to MTB infection in macrophages from RSTR and LTBI individuals. Aim3. Determine ABL and COLEC10 function and MTB-induced transcriptional signatures in alveolar macrophages that are associated with susceptibility or resistance to MTB infection and validate findings in a new cohort of RSTRs. To accomplish this ICIDR's aims we bring together a multidisciplinary and experienced team of long-term collaborating researchers at Makerere University (Mayanja, Mupere) in Kampala (Uganda), Univ. of Washington (Hawn, Seshadri) and Case Western Reserve University (Boom, Johnson, Stein). This ICIDR project will provide capacity building and training opportunities in clinical and laboratory TB research.