Autophagy and T-Cell exhaustion
So far, the treatment of TB has focused almost exclusively on using drugs to directly try to kill the bacteria, but there’s increasing evidence that there may be benefits to targeting the host. TB is very clever and it manipulates the host immune system to its own advantage, so if we could use drugs to help the immune system, then we may be able to make it more effective.
Professor of Medicine (1987)and Head of Department of Medicine University of Cambridge
“It might be that exhausted T cells can’t fight multi-drug resistant TB effectively, in which case we need to find a way to overcome this exhaustion and spur the T cells on to rid the body of the disease,” says Smith.
This is the approach that Professors Ken Smith and Andres Floto from the Department of Medicine at Cambridge, also part of the collaboration, are taking. Smith is looking at the role that specialist immune cells known as T cells play in the persistence of multi-drug resistant strains of TB. His group has evidence that around two thirds of the population have T cells which have a tendency to become ‘exhausted’ when activated.
Professor of Respiratory Biology, Department of Medicine, University of Cambridge
For Professor Floto, the key may lie in the role played by the macrophages and their otherwise voracious appetites. As their Greek name suggests, macrophages ‘eat’ unwanted material (surprisingly similar in action to Pac-Man), effectively chewing it up, breaking it down and spitting it out again
This process, known as autophagy (‘self-eating’), is a repair mechanism for clearing damaged bits of cells and recycling them for future use, but also works as a defence mechanism against some invading bacteria. So why, when it swallows TB, does the bacteria manage to avoid being digested?
“Autophagy is partially inhibited by TB itself, but we found that if you overstimulate this mechanism – like flooring the accelerator of a car – you can overcome the bacteria,” explains Floto. “Clearly this will be applicable to normal TB, but we already have drugs that are effective against this. We want to know if this would work against multi-drug resistant strains.”
Prof Floto and colleagues already have a list of potential drugs that can stimulate autophagy, drugs that have already been licenced and are in use to treat other conditions, such as carbamazepine, which is used to treat epileptic seizures. These drugs are safe to use: the question is, will they work against TB?
“We’ve already shown that carbamazepine stimulates autophagy in cells to kill TB – even multi-drug resistant TB. We now want to refine it and test it in mice and in fish, alongside a shortlist of around 30 other potential drugs,” he adds.