Natural Resistance to Mycobacterium Tuberculosis Infection

对结核分枝杆菌感染的天然抵抗力

• 批准号: 8819988
• 负责人: W. Henry Boom
• 金额: $ 71.97万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819988
• 关键词: Address; Adult; Alveolar Macrophages; Biological Assay; Biological Markers; Biological Neural Networks; Blood; Breathing; Cessation of life; Characteristics; Clinical; Clinical Research; Communicable Diseases; Development; Disease; Epidemiologist; Epidemiology; Failure; Genes; Household; Human; Imatinib; Immune; Immune response; Immunologist; Immunology; In Vitro; Individual; Infant; Infection; Infection Control; Interferons; Knowledge; Laboratories; Light; Lung; Measures; Mediating; Messenger RNA; Mycobacterium tuberculosis; Natural Resistance; Pathogenesis; Pathway Analysis; Pathway interactions; Persons; Pharmacotherapy; Phase; Phenotype; Physicians; Predisposition; Public Health; Pulmonary Tuberculosis; Pulmonology; Relative (related person); Research; Research Personnel; Resistance; Resistance to infection; Risk; Scientist; Testing; Time; Training; Tuberculin Test; Tuberculosis; Tuberculosis Vaccines; Uganda; Universities; Washington; Whole Blood; aerosolized; cohort; drug development; electronic data; experience; follow-up; gene discovery; genetic variant; genome-wide linkage; insight; killings; macrophage; monocyte; multidisciplinary; novel strategies; prevent; public health relevance; research study; residence; resistance gene; resistance mechanism; response; tuberculosis drugs

 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.

 描述(申请人提供)：结核病(TB)是全球主要的公共卫生负担。大多数人在与肺结核患者密切接触后，通过吸入雾化结核分枝杆菌(MTB)而感染。大多数人在没有消除这种感染的情况下控制了这种感染，并通过结核菌素皮肤试验阳性和/或干扰素-释放试验(IGRA)来衡量出现潜伏的结核分枝杆菌感染(LTB I)。在乌干达城市的一项大型结核病家庭接触研究中，我们惊讶地发现，在两年的跟踪调查中，9.1%的密切成人家庭接触者(HHC)的TST持续为阴性。持续的TST阴性状态表明，一些个体可能抵抗和/或快速流产MTB感染。确定结核分枝杆菌感染者(RSTR)免疫反应的特征将有助于确定对结核分枝杆菌的天然耐药机制。RSTR的流行病学风险特征与患有或发展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出的mRNA，我们识别了将RSTR与LTBI患者区分开来的转录特征。具体地说，利用基因集浓缩分析和线性神经网络分析，我们发现伊马替尼-ABL途径和COLEC10基因可能是RSTR和LTBI的不同之处，从而直接参与或标记对MTB的感染。利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。这些结果支持了这种ICIDR的假设，即RSTR具有由巨噬细胞介导的保护性先天免疫反应。这一假设将在三个目标中得到检验。目的：1.确定RSTR表型的长期稳定性，并确定精英RSTR。确定全血结核分枝杆菌杀伤是否区分RSTR和LTBI个体。AIM2.确定候选抗性基因ABL和COLEC10如何调节RSTR和LTBI个体巨噬细胞对MTB感染的反应的机制。Aim3.确定ABL和COLEC10的功能以及MTB诱导的肺泡巨噬细胞中与MTB感染易感性或抵抗力相关的转录特征，并验证在新的RSTR队列中的发现。为了实现ICIDR的目标，我们在大学坎帕拉(乌干达)的Makerere大学(Mayanja，Mupere)汇聚了一支多学科的、经验丰富的长期合作研究团队。华盛顿大学(霍恩，塞沙德里)和凯斯西部储备大学(博姆，约翰逊，斯坦)。ICIDR项目将在临床和实验室结核病研究方面提供能力建设和培训机会。