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

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 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.