Cell death in TB-HIV pathogenesis

Our analysis of whole blood transcriptional and epigenetic signatures from TB/HIV patients has identified the role of multiple cell death pathways in TB progression.

We use in vitro infection models of primary human monocyte-derived macrophages, neutrophils and dendritic cells, to investigate the regulation of pyroptosis, ferroptosis and Neutrophil extracelluar traps (NETosis) during TB-HIV co-infection.

We use a variety of molecular techniques, coupled with single cell analysis by confocal microscopy and Flow-FISH cytometry to identify the regulators of these pathways and their impact on TB-HIV replication. We are also testing numerous small molecule inhibitors to prevent death via these different pathways.

Team members: Nashied Peton, Rachel Lundie, Erya Ni

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-HIV 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 the elusive poly-repeat regions known as PPE/PGRS, and which we can now sequence with PacBio long sequencing, cause some strains to be hyper-inflammatory.

We are investigating the effect of strains with interesting genetic and inflammatory phenotypes on their ability to increase HIV-1 replication during co-infection. We also study whether they associate more with extra pulmonary TB, through their ability to cause greater tissue-destructive cell death.

Team members: Paulo Ranaivomanana, Rachel Lundie, Mthawelanga Ndengane


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: Nomfundo Sibiya, Abhimanyu, in collaboration with the Wellcome Centre for Infectious Diseases in Africa

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 5,400 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: Abhimanyu, Robyn Waters, Nashied Peton, 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).