Australian researchers have discovered a potential antidote to the deadly box jellyfish sting. The paper, published on 30 April in Nature Communications, suggests a cholesterol-lowering drug can block symptoms in mice ― including agonizing pain and scarring ― if applied within 15 minutes of contact with the venom.
Furthermore, the study highlights the advantages of using whole genome CRISPR screening to rapidly discover how venom acts on cells and identify potential new medicines.
The box jellyfish is one of the world’s most venomous marine creature. These lethal jellyfish have about 60 tentacles up to three metres long, holding millions of microscopic venom-filled hooks. They can actively swim, at speeds of up to 7.5 kilometres per hour, mainly feeding in shallow waters. And their dangerous venom can cause excruciating pain and death in just minutes due to a resulting heart attack.
Around 40 people are reported to die each year but the numbers are likely much higher since many cases are not reported. And warming ocean temperatures are only increasing the number of box jellyfish.
The team of researchers, led by Associate Prof Greg Neely and Dr Raymond (Man-Tat) Lau of the University of Sydney in Australia, used something called whole genome CRISPR screening to discover the potential antidote. They first collected Chironex fleckeri, a species of box jellyfish commonly found in Australia and isolated the venom.
Then, they screened groups of immune cells genetically modified with CRISPR to “knock out” certain genes – each group of cells had a different gene missing. Each group of cells was exposed to the venom and cells that survived were screened further to look for common genes and proteins. This allowed the researchers to identify factors in human cells that allow the venom to work.
The screening identified four genes involved in cholesterol production are targeted by the venom. So, the team decided to test whether existing cholesterol-lowering drugs could block the venom – luckily, there are already a huge amount of drugs on the market targeting cholesterol. And they found two: MbCD and HPbCD. The HPbCD drug also blocked symptoms in mice injected with C. fleckeri venom if administered within 15 minutes.
The authors hypothesise that jellyfish venom might need the cholesterol in cell walls to actually enter the cells because the drug hydroxypropyl beta-cyclodextrin or HPbCD works by pulling cholesterol out of the cell membrane.
The antidote seems to work on human cells in the lab and on live mice. Based on the findings, the researchers hope they will be able to develop a topical HPbCD cream for humans.
They know the drug can potentially stop skin necrosis, scarring, and pain, but they don’t yet know whether it can stop a cardiac arrest.
The next step will be to test the antidote on animals exposed to an actual jellyfish sting to determine if the drug can, in fact, protect the animals against the potent sting of a live jellyfish.
(1) Lau, M-T. et al. Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote. Nature Communications (2019). DOI: 10.1038/s41467-019-09681-1