Lab focus: Heterogeneity of tuberculosis and HIV pathogenesis

Our work focuses on understanding how the tuberculosis (TB) bacteria and HIV virus interact within cells to evade the human immune response and cause disease.

The majority of people who get infected with the TB bacteria do not get sick. Yet, also having HIV-1 infection, diabetes or even vitamin D deficiency can increase the risk of developing TB disease, once infected. Our research focuses on understanding how these ‘risk factors’ change the immune cells’ response during infection. We are particularly interested in the different way these pathogens cause infected cells to die and how this destroys the lung and other sites of infection, allowing the bacteria to spread and cause disease. 

Given that tuberculosis is transmitted by coughing, following damage to the lung, the only way to eradicate TB is by stopping people developing disease once infected. We are therefore also identifying new markers for early diagnosis of infection, with the aim to develop drugs targeting the immune defects caused by these ‘risk factors’ which can be used to treat infected people to prevent them from getting sick. 

Research interest

Our research focuses on how the response of innate immune cells which engulf the tuberculosis bacteria, namely macrophages, neutrophils and dendritic cells is dysregulated by known TB risk factors. 

We investigate how the immune response of people with HIV-1 infection, vitamin D deficiency and type 2 diabetes differs during disease and early infection, to understand the different mechanism by which these risk factors may cause disease. We combine analysis of clinical trial samples to identify novel pathways of pathogenesis in humans, with in vitro models of TB and HIV infection to determine the molecular mechanism underlying disease risk.  

This includes genetic and epigenetic changes in both the host and bacteria and how these impact the inflammatory response during infection. We are particularly interested in the regulation of various cell death pathways and the heterogeneity of cellular responses which we probe with single cell techniques and advanced live cell imaging.

We are currently screening small molecule inhibitors to target various pathways of interest which we hope to develop into new preventative treatments for TB. We also conduct biomarker discovery in at-risk populations using whole genome RNAseq and DNA methylation analysis to identify novel blood-based diagnostics for identifying individuals infected and at risk of disease. 

Our goal is to develop a screening tool we can use to identify infected people who will have the greatest benefit from these new preventive therapies, based on their own individual risk profile