Transmitted by aerosol, M. tuberculosis causes a chronic infection which can persist for years without developing into disease; or for roughly 5-15% of infected people and 10 million people annually, it develops into a chronic inflammatory disease, destroying the architecture of the organ it infects. One of the most intriguing immunological phenomena of human TB, and the basis of our innovative approach to identify biomarkers of protection, is that even in communities with the highest level of TB in the world, children aged 5-10 rarely develop TB, despite their high risk of infection.
We have just completed two clinical studies in South Africa. One is a phase 3 trial of vitamin D to prevent M. tuberculosis infection in children and the other is a TB household contact study identifying infected adults who develop TB and those with no evidence of infection. The student will use a systems biology approach combining RNA-seq, ATAC-seq, flow cytometry, proteomics and bioinformatics to identify immune cell phenotypes and functions in children which associate with protection from infection and disease critically needed to inform improved vaccine design and testing.
Our research focuses on how epidemiological risk factors, such as undernutrition, age and sex differences, as well as viral co-infections, particularly HIV-1 and SARS-CoV-2 increase tuberculosis (TB) risk. We study how the response of innate immune cells which engulf the tuberculosis bacteria, namely macrophages and neutrophils, is dysregulated by these risk factors leading to TB disease development. We combine analysis of clinical cohort samples to identify novel pathways of pathogenesis in humans with in vitro infection models to determine the molecular mechanism underlying disease risk. Together this enables us to identify novel therapeutic targets and develop diagnostic biomarkers to improve earlier TB diagnosis and inform who will most benefit from treatment.
We achieve this using a range of cutting-edge techniques to interrogate genetic, epigenetic, transcriptomic and proteomic changes in both the host and bacteria to identify how these impact the inflammatory response during infection. We are particularly interested in regulation of cell death pathways and the heterogeneity of cellular responses due to tissue micro-environmental changes which we probe using single cell omics, spatial omics and advanced live cell imaging techniques.