The role of Mucosal-associated invariant T (MAIT) cells during the innate immune response to Mycobacterium tuberculosis

粘膜相关不变 T (MAIT) 细胞在结核分枝杆菌先天免疫反应中的作用

• 批准号: 10411946
• 负责人: Charles Kyriakos Vorkas
• 金额: $ 18.43万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-06 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411946
• 关键词: Advisory Committees; Antigens; Area; Biological Assay; Biology; CD8B1 gene; Case-Control Studies; Cell Count; Cells; Chemicals; Chronic; Clinic; Coculture Techniques; Communicable Diseases; Communities; Contact Tracing; Cross-Sectional Studies; Data; Development; Development Plans; Diagnosis; Disease; Exposure to; Funding; Genetic Transcription; Goals; Grant; Granzyme; Growth; Haiti; Haitian; Heterogeneity; Household; Human; IL17 gene; Immune; Immunologics; Immunology; Immunotherapy; In Vitro; Incubated; Individual; Infection; Infection Control; Innate Immune Response; Integration Host Factors; Interferons; Investigation; Knowledge; Laboratories; Libraries; Ligands; Literature; Lymphocyte; Medicine; Memorial Sloan-Kettering Cancer Center; Modeling; Morbidity - disease rate; Mucous Membrane; Mycobacterium tuberculosis; Natural Immunity; Patients; Peripheral Blood Mononuclear Cell; Physicians; Play; Primary Infection; Proteins; Publishing; Pulmonary Tuberculosis; Pyruvaldehyde; Recording of previous events; Regulation; Reporting; Research; Research Design; Research Personnel; Research Proposals; Resistance; Resistance profile; Role; Scientist; Site; Sleep; Surface; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Technical Expertise; Testing; Training; Training Programs; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Vaccine Design; Vitamin B Complex; Work; analog; bactericide; base; career; career development; cohort; indexing; insight; interest; macrophage; meetings; member; monocyte; mortality; novel; perforin; resistance mechanism; response; symposium; translational applications; vaccine strategy; volunteer

Project Summary/Abstract Charles Kyriakos Vorkas, MD is a Fellow in Infectious Diseases at Weill Cornell Medicine (WCM) and a member of the Glickman Laboratory, Memorial Sloan Kettering Cancer Center (MSKCC) whose research interests focus upon Innate immunity during Mycobacterium tuberculosis (Mtb) infection. He plans to pursue a career as a physician-scientist in the field of Tuberculosis (TB) immunology. This proposal describes a five-year training program that will provide the candidate with the knowledge and technical skills to achieve this goal. In addition to intensive laboratory-based experimental training, the proposal includes regular meetings with an advisory committee of experts, active involvement in academic conferences, and formal coursework. At the end of the period of support, the candidate will be prepared to embark on a career as an independent investigator. Little is known about the host factors that influence clearance of Mtb infection, control of latency or progression to active disease. The candidates' work will focus on the role of mucosal- associated invariant T (MAIT) cells in innate immunity to Mtb using an ex vivo MAIT cell activation assay in Haitian donors. MAIT cells are MR1-restricted lymphocytes that recognize bacterially- derived Vitamin B metabolites and data suggest that they act early at mucosal surfaces during Mtb infection. The candidate will investigate immune correlates of resistance to Mtb infection through analysis of three Haitian cohorts: (1) active TB patients (2) healthy household contacts of TB patients and (3) healthy community volunteers without reported exposure. The candidate will also screen synthetic MR1 ligand analogs for effects on MR1 regulation and MAIT activation and test if they can restrict bacterial growth through priming MAIT cells in a monocyte-derived macrophage co-culture model of Mtb infection. This study proposes to identify immune correlates of innate resistance to Mtb infection, which may have direct translational applications for TB immunotherapy or vaccine design.

项目总结/摘要 Charles Kyriakos Vorkas医学博士是威尔康奈尔大学传染病研究员 医学（WCM）和Glickman实验室的成员，纪念斯隆凯特琳癌症 中心（MSKCC），其研究兴趣集中在分枝杆菌感染期间的先天免疫 结核病（Mtb）感染。他计划从事医学科学家的职业， 结核病（TB）免疫学。 本提案描述了一个为期五年的培训计划，将为候选人提供 知识和技能，以实现这一目标。除了密集的实验室基础 试验性培训，建议包括与咨询委员会定期举行会议， 专家，积极参与学术会议和正式课程。结束时 在一段时间的支持下，候选人将准备开始作为独立人士的职业生涯。 调查员 关于影响Mtb感染清除的宿主因素， 潜伏期或进展为活动性疾病。候选人的工作将重点关注粘膜的作用- 使用离体MAIT细胞活化在对Mtb的先天免疫中的相关不变T（MAIT）细胞 在海地捐助者中进行检测。MAIT细胞是MR 1限制性淋巴细胞，识别细菌- 衍生的维生素B代谢物和数据表明， 结核病感染。 候选人将通过以下方式研究抗结核病感染的免疫相关性： 分析三个海地队列：（1）活动性结核病患者（2）结核病的健康家庭接触者 患者和（3）未报告暴露的健康社区志愿者。 候选人还将筛选合成的MR 1配体类似物对MR 1的影响 调节和MAIT激活，并测试它们是否可以通过引发MAIT来限制细菌生长 在Mtb感染的单核细胞衍生的巨噬细胞共培养模型中的细胞。 本研究提出鉴定对Mtb感染的先天抗性的免疫相关性， 其可直接翻译应用于TB免疫治疗或疫苗设计。