Macrophages and Resistance to Mycobacterium Tuberculosis Infection in Humans

人类巨噬细胞和对结核分枝杆菌感染的抵抗力

基本信息

批准号：
10551260
负责人：
Jason Simmons
金额：
$ 18.95万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10551260
关键词：
Advisory Committees Affect Antigens Autophagocytosis Award Binding Biological Assay Biological Testing Case/Control Studies Cell membrane Cellular Immunology Clinical Communicable Diseases Complex Data Defect Disease Drug resistant Mycobacteria Tuberculosis Endosomes Ensure Epidemiology Exposure to Funding Gene Expression Profile Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Transcription HIF1A gene Hour Household Human Human Subject Research Hypersensitivity Hypoxia Inducible Factor IRAK1 gene IRF4 gene Immune Immune response Immunologic Sensitization Immunologics Individual Infection Interferon Type II International Laboratories Learning Lysosomes Macrophage Maps Measures Mentors Mentorship Mycobacterium tuberculosis Organism Pathway interactions Patients Peptides Phagocytosis Phagosomes Phenotype Play Process Program Development Proteins Pulmonary Tuberculosis RNA RNA Helicase Receptor Signaling Regulation Research Personnel Resistance Role Signal Transduction Signaling Molecule Structure Structure of parenchyma of lung Study Subject Systems Biology TNF gene Testing Toll-Like Receptor Pathway Toll-like receptors Training Translations Tuberculin Test Tuberculosis Uganda Universities Variant Vesicle Washington Whole Blood Work analytical method antimicrobial career development cohort cytokine design differential expression drug-sensitive follow-up gene network genetic approach genetic association genetic variant improved indexing large datasets latent infection meetings member microbicide monocyte mycobacterial novel rab11 protein receptor recycling resistance gene response trafficking transcriptome transcriptome sequencing transmission process

项目摘要

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) is a leading worldwide infectious killer, in part, due to a large reservoir of latent infection that contributes to ongoing transmission. Yet some individuals resist Mtb infection despite heavy and repeated exposure as indicated by persistently negative tuberculin skin tests (TSTs) and interferon gamma (IFNg) release assays (IGRAs). Elucidation of the mechanisms employed by these human resisters (RSTRs) may yield novel targets for host-directed therapies or identify immune signatures that correlate with host protection. Dr. Simmons’s collaborators longitudinally followed a group of highly-exposed household contacts (HHCs) of index pulmonary tuberculosis (TB) patients in Uganda and define RSTRs as the ~7% that remain TST/IGRA-negative over 8-10 years of follow-up. Using whole transcriptome analysis (RNAseq), Dr. Simmons found that monocyte-derived macrophages (MDMs) from RSTRs versus HHCs with latent Mtb infection (LTBI) have distinct transcriptional responses after ex vivo Mtb infection. He further identifies a network of genes differentially expressed in RSTR versus LTBI macrophages. Gene products of this RAB11 network play roles in intracellular phagosome or vesicle trafficking. Common polymorphisms in one of these genes, YTHDC2, were found to associate with protection from TB disease in Uganda but the immunologic mechanisms are unknown. The long-term objectives of this proposal are to define macrophage pathways or genes that characterize the protective RSTR response. Dr. Simmons will determine whether RAB11 network candidate resistant genes are required for microbicidal activities of phagosome pathways in Aim 1, and confirm these phagosome processes are distinct in primary RSTR and LTBI macrophages. In Aim 2, he proposes genetic approaches to identify natural variants in the RAB11 network gene YTHDC2, fine map the functional polymorphism(s), and measure the impact that relative YTHDC2-deficiency has on phagosome maturation and other macrophage responses to Mtb. Once the immune signatures and cellular effectors are identified in this unique cohort of human RSTRs, host-directed therapies that augment these protective functions can be developed to improve the efficacy of currently available antimicrobials. Dr. Simmons is currently a Senior Fellow in the Division of Allergy and Infectious Diseases at the University of Washington. He additionally proposes a comprehensive career development program that includes: 1) Mentored training and formal didactics in large data set analyses (e.g. statistical genetics, systems biology); 2) mentorship in design of case-control studies and human subjects research; 3) structured opportunities to present his work to local and international scientific audiences; and 4) Scientific Advisory Committee meetings that ensure scientific and career development progress. By the conclusion of this award, Dr. Simmons will transition to an independently-funded expert in the Mtb host response who will direct his own laboratory.

项目摘要结核分枝杆菌（MTB）是全球领先的传染性杀手，部分原因是大量的水库潜在感染有助于持续传播。但是有些人抵制MTB感染目的地持续的负结核蛋白皮肤测试（TST）和干扰素持续的负面暴露和重复暴露伽玛（IFNG）发布测定法（IGRAS）。阐明这些人类抗议者携带的机制（RSTR）可能会产生用于宿主定向疗法的新目标，或确定与之相关的免疫特征主机保护。西蒙斯博士的合作者纵向跟随一群暴露的家庭乌干达索引肺结核（TB）患者的联系（HHC），并将RSTR定义为〜7％在8 - 10年的随访中，保持TST/IGRA阴性。使用整个转录组分析（RNASEQ）博士西蒙斯发现，来自RSTR的单核细胞衍生的巨噬细胞（MDMS）与具有潜在MTB的HHC 离体MTB感染后感染（LTBI）具有不同的转录反应。他进一步确定了基因网络在RSTR与LTBI巨噬细胞中的表达不同。该rab11的基因产物网络在细胞内吞噬体或蔬菜贩运中扮演角色。其中一种的常见多态性发现基因YTHDC2与乌干达的TB疾病的保护相关，但免疫学机制是未知的。该提议的长期目标是定义巨噬细胞途径或表征受保护的RST响应的基因。 Simmons博士将确定Rab11网络是否 AIM 1中吞噬体途径的杀菌活性需要候选抗性基因，并确认这些吞噬体过程在原发性RSTR和LTBI巨噬细胞中是不同的。在AIM 2中，他的建议识别Rab11网络基因ythdc2中自然变异的遗传方法，细微绘制功能多态性（S），并衡量相对YTHDC2缺乏对吞噬体成熟和其他巨噬细胞对MTB的反应。一旦在此确定了免疫特征和细胞效应独特的人类RSTR，宿主指导的疗法可以增强这些受保护功能开发以提高当前可用的抗菌剂的效率。 Simmons博士目前是大学过敏和传染病的高级研究员华盛顿。他还提出了一个全面的职业发展计划，其中包括：1）大型数据集分析中的指导培训和形式教学学（例如统计遗传学，系统生物学）； 2）病例对照研究和人类受试者研究设计的遗传； 3）结构化的机会向当地和国际科学观众介绍他的作品； 4）科学咨询委员会会议这确保科学和职业发展进步。根据该奖项的结论，西蒙斯博士将过渡到MTB主机回应中的独立资助的专家，他们将指导自己的实验室。