Studies of Mucosal Associated Invariant T (MAIT) cells in people with HIV, TB and HIV/TB co-infection in South Africa

 描述(申请人提供)：结核病(TB)，由艾滋病毒助长，是世界上感染性死亡的主要原因。开发一种有效的疫苗是公共卫生的优先事项，需要极大地改善我们目前对人类结核病免疫的了解。候选人是一名传染病专家，长期致力于撒哈拉以南非洲地区艾滋病毒和结核病的学术研究。她提出了一个独特的职业发展计划，她将在夸祖鲁-纳塔尔结核病和艾滋病毒研究所(K-RITH)度过大部分时间，霍华德·休斯医学院和夸祖鲁-纳塔尔大学之间的合作创建了一个最先进的研究设施，将尖端实验室技术和国际公认的科学调查人员带到南非德班结核病和艾滋病毒流行的核心。 候选人提出了一项为期5年的培训和指导性研究计划，在此期间，她将对健康对照和艾滋病毒、结核病以及艾滋病毒/结核病合并感染者的肺部和外周粘膜相关不变T细胞(MAIT)进行深入研究。她的研究和职业发展将由她在K-RITH的主要导师Thumbi Ndung‘u教授密切指导和监督，Thumbi Ndung’u教授是一位在国际上受人尊敬的、多产的和资金充足的科学家，他利用德班具有良好特征的艾滋病毒和结核病队列研究宿主病原体免疫动力学。此外，候选人将由人类结核病免疫学和MAIT细胞领域的领军人物大卫·莱温松博士和艾滋病毒疫苗免疫学专家布鲁斯·沃克博士指导，布鲁斯·沃克博士十多年来在德班建立和保持了卓有成效的科学合作。这位导师和候选人已经设计了一个在美国授课的细胞免疫学和翻译免疫学课程的培训计划，这将填补她知识的空白，并使她能够在获奖期结束时成功地与受过博士培训的免疫学家竞争。 MAIT细胞是她研究的重点，是一类令人兴奋的天然淋巴细胞，由微生物产生的维生素B代谢物激活，并受到非多态和高度保守的MHC相关分子MR-1的限制。体外和动物研究表明，MAIT细胞在人类肺对结核分枝杆菌的保护性免疫反应中发挥作用。有趣的是，MAIT细胞从人的血液循环中急剧和不可逆转地耗尽 艾滋病毒感染。根据他们的初步结果，研究小组预计会发现，在HIV感染中，由于微生物易位、慢性MAIT细胞激活以及抑制共刺激分子程序性死亡-1(PD-1)的潜在可逆上调，肺部MAIT细胞的Th1样和溶细胞功能被取消。候选人将使用尖端和经典的免疫学技术来检验这一假设，她将在K-RITH和美国导师的实验室中学习这些技术。到五年培训期结束时，候选人将获得她所需的知识、科学经验和出版物，以成功启动一个独立实验室，重点研究艾滋病毒和结核病的人类免疫学翻译，目标是为开发保护性结核病疫苗和/或免疫治疗战略做出贡献，以提高艾滋病毒感染者抵抗结核分枝杆菌的能力。

 DESCRIPTION (provided by applicant): Tuberculosis (TB), fuelled by HIV, is the leading cause of infectious death in the world. Development of an effective vaccine is a public health priority and requires great improvement on our current understanding of human TB immunity. The candidate is an Infectious Diseases specialist with a longstanding commitment to academic research into HIV and TB in sub-Saharan Africa. She proposes a unique career development plan in which she will spend the majority of her time at the KwaZulu-Natal Research Institute for Tuberculosis and HIV (K‐RITH) where a collaboration between the Howard Hughes Medical Institute and the University of KwaZulu-Natal has created a state‐of-the-art research facility tht brings cutting-edge laboratory technology and internationally-recognized scientific investigators to the heart of the TB and HIV epidemics in Durban, South Africa. The candidate proposes a 5-year plan of training and mentored research during which she will perform intensive studies on lung-resident and peripheral Mucosal Associated Invariant T (MAIT) cells in healthy controls and people with HIV, TB and HIV/TB co-infection. Her research and career development will be closely guided and supervised by her primary mentor at K-RITH, Prof. Thumbi Ndung'u, an internationally respected, productive and well-funded scientist who studies host‐pathogen immune dynamics using well‐characterized HIV and TB cohorts in Durban. Additionally, the candidate will be mentored by Dr. David Lewinsohn, a leader in the field of human TB immunology and MAIT cells, and by Dr. Bruce Walker, an expert in HIV vaccine immunology who has established and maintained very productive scientific collaborations in Durban for more than a decade. The mentors and candidate have designed a training program of didactic US-based coursework in cellular and translational immunology that will fill in the gaps in her knowledge and allow her to successfully compete with PhD-trained immunologists by the end of the award period. MAIT cells, the focus of her research, are an exciting class of innate lymphocyte that are activated by microbially produced Vitamin B metabolites and restricted by the non-polymorphic and highly conserved MHC-related molecule, MR-1. In vitro and animal work suggests that MAIT cells play a role in the human lung's protective immune response against M.tb. Interestingly, MAIT cells are acutely and irreversibly depleted from the circulation of people with HIV infection. Based on their preliminary results the research team expects to find that the Th1-like and cytolytic functions of lung-resident MAIT cells are abrogated in HIV-infection due to microbial translocation, chronic MAIT cell activation and potentially reversible up-regulation of the inhibitory co-stimulatory molecule Programmed death-1 (PD-1). The candidate will test this hypothesis using cutting-edge and classical immunology techniques that she will learn in the labs of her K-RITH and US-based mentors. By the end of the five year training period, the candidate will have gained the knowledge, scientific experience and publications she needs to successfully launch an independent laboratory that will focus on translational human immunology of HIV and TB with the goal of contributing to the development of a protective TB vaccine and/or immunotherapeutic strategies to improve the ability of HIV-infected people to resist M.tb.