Neutrophils are the most abundant component of the innate immune system and contribute a vital role in controlling infection. This role includes the formation of neutrophil extracellular traps (NETs) which contain and destroy invading pathogens extracellularly. Formed of DNA, histones and neutrophil granular proteins, NET formation (NETosis) is now understood to be triggered by multiple pathogens, including Mycobacterium tuberculosis the leading causes of global mortality caused by a single pathogen.
Whilst NETs are designed to trap and kill pathogens, their granule-derived components also degrade tissues and cause inflammatory tissue damage. The student will use a combination of advanced imaging technologies, flow cytometry, proteomics, clinical pathogen variants and co-culture cellular models to investigate bacterial and neutrophil functional differences that impact NET composition with bacterial killing vs. tissue destructive capacity associated with protective vs. destructive disease outcomes.
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.