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（由适用提供）：结核病（TB）是全球主要的公共卫生。与肺结核密切接触后，大多数人被吸入雾化的结核分枝杆菌（MTB）感染。大多数通过消除阳性结核蛋白皮肤测试（TST）和/或干扰素释放分析（IGRA）测量，控制了这种感染，而无需消除它并发展潜在的MTB感染（LTBI）。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，在随访的两年中，有9.1％的成年家庭接触（HHC）仍然是持续的TST负面影响。持续的TST负状态表明，某些人可以抵抗和/或快速流产MTB感染。抵抗MTB感染（RSTR）的人的免疫反应的表征将使自然电阻机制鉴定为MTB。 RSTR的流行病学风险特征与患有或开发LTBI的HHC没有显着不同。使用从MTB感染的血液衍生的单核细胞中分离出的微阵列和mRNA，我们确定了将RSTR与LTBI患者区分开的转录特征。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imatinib-abl途径和CoLEC10基因可以将RSTR与LTBI区分开，因此直接参与了对MTB感染的抗性或抗性标志。使用全基因组连锁研究，我们还发现了将RSTR与LTBI患者区分开的先天免疫病变中的基因变异。这些结果支持了该ICIDR的假设，即RSTR保护了由巨噬细胞介导的先天免疫回报。该假设将以3个目标进行检验。 AIM1。确定RSTR表型的长期稳定性并识别精英RSTR。确定全血MTB是否杀死RSTR与LTBI个体区分。 AIM2。确定候选抗性基因ABL和COLEC10如何调节RSTR和LTBI个体巨噬细胞中MTB感染的反应的机制。 AIM3。确定与MTB感染的易感性或抗性相关的肺泡巨噬细胞中ABL和COLEC10功能以及MTB诱导的转录特征，并在新的RSTR中验证发现结果。为了实现ICIDR的目标，我们将位于Univ的坎帕拉（Uganda）的Makerere University（Mayanja，Mupere）的长期合作研究人员组成了多学科和经验丰富的团队。华盛顿（Hawn，Seshadri）和Case Western Reserve University（Boom，Johnson，Stein）。这个ICIDR项目将在临床和实验室结核病研究中提供能力建设和培训机会。