Discovering the immunological and environmental drivers of subclinical tuberculosis

• Graduate Research Masters
• PhD

Transmitted by aerosol, Mycobacterium tuberculosis causes a chronic infection that in roughly 5-15% of infected people, and 10 million people annually, which develops into a chronic inflammatory disease called tuberculosis (TB) that destroys 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 immune mediators of TB risk and protection, is that even in communities with the highest level of TB in the world, children aged 5-10 rarely develop TB, despite high rates of infection, whilst young adults are most at risk of developing and transmitting TB.

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 or disease. Using high-resolution PETCT imaging of these individuals we showed that most adults who progress to TB have an asymptomatic subclinical form of disease that can last up to 4 years before clinical diagnosis.

This project will investigate how differences in immune cells, the lung microbiome and the inflammatory environment of these tissues differ between people we remain protected and those who develop disease. Using lung and blood samples collected from these longitudinal cohorts, 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 which associate with protection from infection and development of disease critically need to inform improved vaccine design and biomarkers for screening and therapeutic monitoring.

Epidemiological, geospatial, and clinical imaging data will also be investigated to identify environmental and demographic determinants of subclinical TB development, to inform design of community based subclinical TB screening strategies to improve early TB detection and treatment.

Our research focuses on identifying and correcting immunological dysfunction that causes tuberculosis. We combine analysis of clinical cohort samples and epidemiological data to identify environmental drivers and novel pathways of pathogenesis in humans, with infection model systems to determine the molecular mechanism underlying disease risk. We study how environmental and demographic risk factors, such as undernutrition, age, sex, and viral co-infections, particularly HIV-1 and SARS-CoV-2, impact immune function to increase tuberculosis 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 development. 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 when we take these into clinical trial.

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 macro and microenvironmental changes which we probe using single-cell omics, spatial omics and advanced live cell imaging techniques.