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Project Topic
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Over 10 million people developed TB in 2015, and almost 2 million people died of TB that year. TB is the leading cause of death in HIV-infected persons in Africa. In high burden countries like South Africa, almost 1 in every 100 people develops TB each year, and HIV prevalence in new TB cases was approximately 60% in 2015. HIV co-infection increases the risk of developing TB by up to 30 times. Notably, this heightened susceptibility to TB is increased even before profound CD4+ depletion. The need for tools to prevent TB transmission and disease is greater than ever. An effective vaccine and biomarkers to identify those at greatest risk of disease will be key to reducing TB. The challenge with developing these interventions is our incomplete understanding of the drivers of disease. Along with a refinement of our understanding of TB as a spectrum of infection and disease states, we need more knowledge of the host-pathogen relationships that contribute to different states. TB and HIV co-infection presents an opportunity to study defects in immunity that increase risk of TB disease. To date, studies have largely focused on Th1 responses (particularly IFN-?), which are undoubtedly important in protective TB immunity. However, IFN-?-independent mechanisms may also contribute to, or synergise with, Th1 responses to TB. We present novel data that CD4+ T cells producing the cytokine Interleukin-22 (IL-22), or 'Th22' cells, make up a major part of the human immune response to Mycobacterium tuberculosis (Mtb), are a distinct subset from IFN-?/IL-17-producing cells, and are severely depleted during HIV infection. Given these findings, we propose a comprehensive characterisation of Mtb-specific Th22 cells along the spectrum of TB infection, disease and treatment, in the context of HIV co-infection. We propose to study (1) Th22 responses during active TB disease and treatment, (2) the restoration of Th22 cells during HIV infection and ART, and (3) Mtb-specific Th22 cells over the spectrum of TB infection and disease states. We will comprehensively assess the balance of Th22, Th1 and Th17 responses to Mtb, in carefully designed clinical cohorts. These studies will contribute to building clinical research capacity of two PhD students, one MSc student and one Postdoctoral fellow, and the further career development of the Senior Fellow. This project will advance scientific knowledge on the major poverty-related diseases, TB and HIV, and has potential to contribute to the development of effective TB vaccines and predictive biomarkers.
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