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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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) 和格利克曼实验室成员，纪念斯隆凯特琳癌症中心中心（MSKCC），其研究兴趣集中于分枝杆菌期间的先天免疫结核病（Mtb）感染。他计划在以下领域从事医学科学家的职业结核病（TB）免疫学。该提案描述了一个为期五年的培训计划，将为候选人提供实现这一目标的知识和技术技能。除了基于密集实验室的实验性培训，该提案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。结束时在支持期内，候选人将准备好以独立的身份开始职业生涯研究者。对于影响 Mtb 感染清除、控制 Mtb 感染的宿主因素知之甚少。潜伏期或进展为活动性疾病。候选人的工作将集中于粘膜的作用使用离体 MAIT 细胞激活对 Mtb 的先天免疫中相关的不变 T (MAIT) 细胞在海地捐献者中进行检测。 MAIT 细胞是 MR1 限制性淋巴细胞，可识别细菌- 衍生的维生素 B 代谢物和数据表明，它们在早期就在粘膜表面发挥作用。结核分枝杆菌感染。候选人将通过以下方式研究 Mtb 感染抵抗力的免疫相关性：对三个海地队列的分析：(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) 没有报告接触的健康社区志愿者。候选人还将筛选合成的 MR1 配体类似物对 MR1 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 Mtb 感染的单核细胞来源的巨噬细胞共培养模型中的细胞。这项研究旨在确定对结核分枝杆菌感染的先天抵抗力的免疫相关性，这可能对结核病免疫治疗或疫苗设计有直接的转化应用。