Africa Health Research Institute (AHRI) celebrated two new PhD graduates at the University of KwaZulu-Natal’s May 2023 graduation ceremony.

Dr Magalli Magnoumbas project was titled ‘Investigating the development of T-cell immunity to HIV and TB through analysis of the TCR repertoire in blood and tissue’.

Supervised by AHRI faculty member Dr Al Leslie, Magalli’s project took advantage of new developments in TCR sequencing technology and bioinformatics to study the T-cell response to infection in a comprehensive and unbiased way. When humans are infected with pathogens such as HIV and TB, specialised cells in the body called T-cells expand to fight the infection. These cells recognise parts of the pathogen through a highly diverse set of receptors on their cell surface called T-cell receptors (TCRs). To make a good vaccine it is important to figure out which bits of a pathogen are most well recognised. Standard ways of doing this in the lab are time consuming and require many samples from patients.

The idea of Magalli’s project was to use a sequencing approach to identify which TCRs expand in people infected with TB and HIV and then use computer analysis to work out which part of the pathogen these TCRs recognise. Importantly, this approach only uses a small amount of DNA or RNA and it is completely unbiased. In this way, she was able to study the T-cell responses to acute HIV infection and TB-specific T-cells present in TB infected lung. Unfortunately, Covid restrictions prevented her from finishing the last part of the thesis and identifying individual peptides. However, the project is a good proof of concept and should be a valuable approach in the future for monitoring natural and vaccine induced immunity.

Magalli, who says she was delighted to graduate, is now working for Gilead in Foster City in the USA, in the field of HIV virology.

Dr Kimone Fisher’s project was titled ‘Investigating Netosis-associated proteins in human TB granulomas as targets for host-directed therapies and prediction of disease progression’.

Describing what causes lung damage when someone is infected with tuberculosis (TB) is vital in order to identify potential host-directed therapies (HDT). Host-directed therapies may boost current TB treatment protocols (which target the actual pathogen) by targeting human proteins that promote lung damage.

Kimone, who was supervised by AHRI faculty member Dr Mohlopheni Marakalala, found that:

  1. IP-10 in the TB group at both the mRNA and protein level is elevated and may be used as a biomarker of disease progression to discriminate between latent TB infection and TB disease.
  2. NETosis is mechanistically associated with TB disease severity and is enriched in caseum.
  3. Targeting these NETosis associated pathways with pharmaceutical inhibitors significantly reduced NETosis. Furthermore, NETosis associated genes associate with clinical disease.
  4. Finally, GSDMD is detectable in the plasma of those with latent TB and TB disease and is enriched in the inflammatory rings surrounding caseum and does not colocalize with NETosis proteins observed in lung necrotic lesions.

(Above: Dr Kimone Fisher with her supervisor, AHRI faculty member Dr Mohlopheni Marakalala)

Ultimately, her data shows evidence that NETosis (a unique form of cell death) is a driver of lung pathology in TB, and provides evidence that NETosis is a potential target for host-directed therapy.

“I am elated to finally have my PhD in medical science,” said Kimone. “It’s been a long road, filled with challenges, trials and triumphs but I’m so glad and blessed that this journey is finished and the next one has begun.”

Kimone is continuing her career in TB research, and is currently working at Imperial College in London, UK, as a research associate.

(Top photo: Dr Magalli Magnoumba and Dr Kimone Fisher)