Maria Burke
Researchers have conducted a genome-wide Crispr screen of the world's deadliest mushroom.
Researchers have found an antidote to the toxin produced by the world’s deadliest mushroom. They identified a diagnostic agent, already approved by the US FDA, which targets a key protein in the toxin.
The death cap (Amanita phalloides) is responsible for 90% of mushroom-related deaths. Its most lethal component is α-amanitin, which can cause fatal damage to the liver and kidneys. However, exactly how α-amanitin poisons humans remains unclear, which makes developing a specific antidote challenging.
The team, involving Qiao-ping Wang of Sun Yat-sen University in Shenzhen, China, and Greg Neely of the University of Sydney, Australia, have already used Crispr to work out the molecular mechanisms of deadly jellyfish venom, leading to a potent antidote.
In this study, they performed a genome-wide Crispr screen to identify genes and pathways involved in α-amanitin toxicity. They found that several novel pathways including N-Glycan biosynthesis (connected with protein folding and function) were involved in cell death. They then showed that the enzyme STT3B, a key component of this pathway, was required for toxicity.
Using virtual drug screening techniques, the team identified 34 potential antidotes. They were surprised to discover that a drug already approved by the FDA appeared to block STT3B. Indocyanine green (ICG), a fluorescent iodide dye, is used to diagnose liver disease and test eye function. In human cells and mice, it blocked toxic effects and helped the cells and animals survive.
The best results came when mice were treated four hours after ingesting α-amanitin; those who received ICG after eight or 12 hours didn’t get the same benefits. The toxin may have caused irreversible damage, the researchers suggest.
Anne Pringle of the University of Wisconsin-Madison, US, says the paper is a good starting point but whether ICG will work in humans remains to be seen. ‘The fact that they tested it in a mouse model is good because that’s a lot more than I’ve seen with some of these other ideas that have come and gone. But human trials are tricky because you can’t feed people mushrooms and then try to cure them. The only way to test effectiveness is to wait until someone comes into a hospital after having eaten a death cap.’
Meanwhile, the researchers believe that their method of combining genome-wide Crispr screening with virtual drug screening could help to quickly identify new antidotes for other medically relevant human poisons.
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