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

项目摘要/摘要 查尔斯·基里亚科斯·沃卡斯，医学博士，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(MSKCC)，其研究兴趣集中在分枝杆菌的天然免疫 结核病(Mtb)感染。他计划在以下领域从事内科科学家的职业生涯 结核病免疫学。 该提案描述了一项为期五年的培训计划，该计划将为应聘者提供 实现这一目标所需的知识和技能。除了以密集的实验室为基础 在试验性培训方面，该提案包括定期与 专家，积极参与学术会议和正式的课程作业。在结束时， 在支持期内，候选人将准备以独立人士的身份开始职业生涯 调查员。 对影响结核分枝杆菌感染清除的宿主因素知之甚少，控制 潜伏期或进展为活动性疾病。候选人的工作重点将放在粘膜的作用上- 利用体外MAIT细胞激活实现对结核分枝杆菌的天然免疫 海地捐赠者的化验结果。MAIT细胞是受MR1限制的淋巴细胞，能识别细菌- 衍生的维生素B代谢物和数据表明，它们在早期作用于粘膜表面 结核分枝杆菌感染。 候选人将通过以下途径研究结核分枝杆菌感染的抵抗力的免疫相关性 海地三个队列的分析：(1)活动性结核病患者(2)健康家庭接触者结核病 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来抑制细菌生长 结核杆菌感染的单核巨噬细胞共培养模型中的细胞。 这项研究建议确定对结核分枝杆菌感染的先天抵抗力的免疫相关性， 它们可能直接用于结核病免疫治疗或疫苗设计的翻译应用。

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.