Our work focuses on understanding how the tuberculosis (TB) bacteria, SARS-CoV-2 and HIV viruses interact within immune cells to 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. We are now also asking whether SARS-CoV-2 co-infection can lead to a similar increased TB risk. 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.
Our analysis of whole blood transcriptional and epigenetic signatures from TB, HIV and COVID-19 patients has identified the role of multiple cell death pathways in disease risk.
We use in vitro infection models of primary human monocyte-derived macrophages and neutrophils to investigate the regulation of pyroptosis, apoptosis and extracellular trap formation during TB, HIV and SARS-CoV-2 infection.
We use a variety of molecular techniques, coupled with single-cell analysis by confocal microscopy, super-resolution microscopy, Totalseq, and spectral cytometry to identify the regulators of these pathways and their impact on inflammatory programmed cell death.
We are also testing numerous small molecule inhibitors to prevent death via these different pathways.
Team members: George Ashdown, Dylan Sheerin, William Vo, Kha Phan, Aisah Amelia Resti, Catherine Chen, Nashied Peton, in collaboration with the Pellegrini Lab, the Mueller Lab, and the Centre for Dynamic Imaging at WEHI, and the Poon Lab at La Trobe University.
Humans have co-evolved with Mycobacterium tuberculosis (Mtb), such that different strains can be found in different regions of the world, and these have been classified into ancient and modern lineages. Some ‘modern’ strains have been shown to be more inflammatory than others.
We are testing whether genetic variations in lipid metabolizing genes which would affect the bacterial cell wall, as well as secreted virulence factors under the control of various ESX systems, cause some strains to be hyper-inflammatory.
We are investigating the effect of strains with interesting genetic and inflammatory phenotypes on their ability to modulate the composition of phagocyte cell membranes as well as impact the replication co-infecting viruses (HIV-1 and SARS-CoV2). We also study whether the ability of different Mtb strains to cause greater tissue-destructive cell death associates with differences in pulmonary and extra pulmonary TB presentation.
Team members: George Ashdown, Dylan Sheerin, William Vo, Mthawelanga Ndengane, in collaboration with the Bahlo Lab at WEHI; Dr Ranaivomanana and Prof Rakootosamimanana at Institute Pasteur Madagascar.
Working in South Africa, we are currently conducting a household contact study of individuals who live with people with drug-resistant TB.
Using a highly sensitive screening technology called 18Fluorodeoxyglucose positron emission and computerised axial tomographic scanning (PET/CT), we are identifying household members with subclinical stages of infection. This is imaging on their lungs or lymph nodes which may indicate they have a current infection, whilst they have not yet developed symptoms of disease.
We are using whole genome RNAseq and DNA methylation analysis to develop and validate a biosignature for recent infection or re-infection that may be of great utility for clinical studies designed to test preventative therapies.
Team members: Dylan Sheerin, Nomfundo Sibiya, in collaboration with Professor Robert Wilkinson at the Wellcome Centre for Infectious Diseases in Africa, Associate Professor Hanif Esmail at University College London, Dr Abhimanyu at Baylor College of Medicine, Associate Professor Evan Johnson at Boston University, Professor Padmini Salgame at Rutgers University
We have shown that deficiency in serum vitamin D impairs the innate and adaptive immune responses to M. tuberculosis and HIV infection, increasing pathogen replication in infected cells and increasing a broad inflammatory response. In order to understand the mechanism of vitamin D regulation we are studying the seasonal changes in DNA methylation in blood cells and how vitamin D supplementation modifies these epigenetic changes.
With the idea that vitamin D can enhance innate immunity to prevent M.tb infection, we are collaborating on a Phase III Trial randomizing 5400 children to receive either weekly vitamin D or placebo, for three years. We are investigating whether and how vitamin D modifies the ability of innate and adaptive immune cells from these children to control bacterial replication.
Project resource: VidiKids is a Phase 3 trial of vitamin D to prevent TB in children, in Cape Town, South Africa.
Team members: Dylan Sheerin, William Vo, Robyn Waters, Nashied Peton, Mthawelanga Ndengane, in collaboration with the Wellcome Centre for Infectious Diseases in Africa, Adrian Martineau at Queen Mary University of London (Trial PI), and Dr Keren Middlekoop at Desmond Tutu HIV Centre (Site PI).
Enquiries from clinicians interested in entering medical research are encouraged.
My team at WEHI investigates cellular and molecular mechanisms of TB pathogenesis, by reverse translating our findings from clinical research conducted by my team at the Wellcome Centre for Infectious Diseases Research in Africa, at University of Cape Town (UCT), South Africa.
We collaborate at WEHI with Professor Seth Masters, Associate Professor James Vince, and Dr Rebecca Feltham on infection models of cell death, Professor Melanie Bahlo and Associate Professor Matt Ritchie for bioinformatic analyses, and work closely with the Centre for Dynamic Imaging, Genomics and Proteomic Facility teams.
We have international collaborators to University College London, Imperial College London, Boston University, Rutgers University, Queen Mary’s University of London, Stellenbosch University and Institute Pasteur Madagascar.