Issue 1 • 2022
© 2022 The Royal Australasian College of Physicians
In the search for new tuberculosis treatments, researchers have turned to look within
Tuberculosis remains a leading cause of death across the world, taking the lives of over 1.5 million people in 2020 alone. A key hurdle to reducing deaths from tuberculosis has been a rising resistance to antibiotics – which has created antibiotic resistant strains in several countries.
This could all be changed after a new development by a team of researchers, led by RACP Fellow, Professor Marc Pellegrini.
One quarter of the world’s population is already infected with the bacterium that can cause tuberculosis and spread once the disease becomes ‘active’ within an individual. Approximately 10 million people have an active illness, often caused by an individual’s own immune system, where tuberculosis-infected macrophages (immune cells) trigger other immune cells to attack them.
Active tuberculosis is more common in people who:
  • have a weakened immune system, particularly those with HIV infection
  • are malnourished
  • have diabetes
  • smoke
A recent study by the Walter and Eliza Hall Institute of Medical Research (WEHI) has found the best way to combat this may be lying dormant in patients themselves, and that eliminating infection could be possible by jumpstarting one’s immune system.
The WEHI study, led by RACP Fellow Professor Marc Pellegrini, shows how cells infected with tuberculosis bacteria are at times tolerant of the pathogen, allowing it to multiply, but the cells can be pushed to ‘commit suicide’, killing themselves and the bacteria. This altruistic form of cell death is called apoptosis and it is an important defence against intracellular pathogens. It was shown that new medicines can coerce infected cells to die, and that this decreased the severity of the disease in a preclinical model.
'The tuberculosis bacteria and humans have co-evolved over hundreds if not thousands of years. The bacteria need to replicate inside our immune cells within our lungs,' Professor Pellegrini explained.
'The bacteria have developed mechanisms to avoid alarming our cells and they can remain relatively dormant, and this is why some of our immune cells unwittingly tolerate the pathogen.'
In observing preclinical models, researchers were able to demonstrate the role of apoptosis in tuberculosis infections by sequentially deleting key effectors. Results subsequently showed that tuberculosis-infected cells could die by apoptosis but they would benefit from an extra push. Attention then turned to methods that could convince infected cells to commit suicide without harming uninfected cells. A drug that was designed to inhibit IAPs, or cell death-regulatory proteins, was able to achieve this.
The preclinical trials of this drug were replicated multiple times with the same beneficial effect –opening a new door to tuberculosis treatment and potentially reducing the difficulties of antibiotic resistance.
'Unlike antibiotics, which directly kill bacteria, IAP inhibitors kill the cells that the tuberculosis bacteria need to survive,' Professor Pellegrini said.
'The beauty of using a host-directed therapy is that it doesn’t directly target the microbe, it targets a host process. By targeting the host rather than the microbe, the chances of resistance developing are incredibly low.'
Attention will now turn towards designing more of these IAP inhibitor drugs. This will include assessing their safety profile and potentially progressing them to clinical trials.
© 2021 The Royal Australasian College of Physicians