Cell death in TB, HIV and COVID-19

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.

Image taken from live-cell imaging
We’re using live cell imaging to track cellular interactions during TB (green)-HIV (yellow) co-infection. When HIV infects macrophages, cells fuse together making giant cells with multiple nuclei (blue).


M. tuberculosis strain variation in TB pathogenesis

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.

Identifying biomarkers of subclinical TB

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

Vitamin D host-directed therapy for TB-HIV

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).