Achilles heel probe for deadly fungus

Scientists at Maynooth have discovered a new way to attack a dangerous fungus that causes infections in seriously ill patients

CONTROLLING a pathogen can be a game of tactics. If you identify a strategy the organism uses to nobble the human defences and establish an infection, then in theory you can develop a way to block it.

A group at NUI Maynooth (NUIM) has accomplished this, finding a possible way to tackle the dangerous fungal pathogen Aspergillus fumigatus. By disrupting a single gene, the fungus becomes sensitive to its own toxin.

The fungus can cause severe disease in immunocompromised people, including cancer and transplant patients. But finding a useful drug for this or any fungal infection is not always easy, according to Sean Doyle, a professor of biology at NUIM.

“The kernel of the issue is that the drugs that are available to treat fungal infections in general, and Aspergillus infections in particular are expensive, and they are not always effective,” he says. “And a lot of the anti-fungal drugs do have severe side-effects in humans.”

Part of the challenge is that at a cellular level fungi have certain similarities with humans. “They are quite complex, and they are more like us than bacteria are. So you are trying to find small differences between our biochemistry and the biochemistry of the fungus, and you have a narrower window to look at to find anti-fungal drugs,” says Doyle.

"The range here is very small and that's why we are interested in Aspergillusto see if we can find new Achilles heels that maybe we can use to attack the fungus."

To find that chink in the armour, they zoned in on gliotoxin, a molecule the fungus makes and releases to help it bypass the host’s immune system and establish an infection.

“What struck us is how could the fungus protect itself against this molecule, because it’s also a eukaryotic cell like humans,” says Doyle. “We couldn’t quite understand how the fungus was able to make it and protect itself.”

Aspergillusalso ploughs quite a bit of effort into making the toxin, he adds. "There are 13 genes involved in making this small molecule. We thought: why is the fungus investing so much energy and time in making this molecule? Was the fungus playing a high-risk game, that it was it making this molecule to enable the infectious process but it could be damaged by it too?"

So they started to look for the organism’s self-defence mechanism against its own toxin, disrupting the key genes involved and seeing what happened. And when they targeted a gene called GliT, they struck gold.

“We deleted the GliT gene and we found the fungus became sensitive to gliotoxin,” says Doyle, who worked with other groups at NUIM and Innsbruck Medical University on the project. “That was the first observation that anyone had made about a gene which was protecting against this particular toxin.”

In addition, once GliT was no longer working as normal, the fungus could not secrete the gliotoxin molecule. "So not only did it appear that this gene was important in protection but it also had a role in either making gliotoxin or getting it out of the cell," says Doyle of the findings, which were published in PLoS Pathogens.

Identifying this role for GliT could point to developing ways of stopping Aspergillus fumigatusin its tracks, and it opens up possibilities for similar genes in other disease-causing fungi, according to Doyle, whose research received funding from PRTLI, the EU and from Enterprise Ireland.