Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote

Man-Tat Lau, John Manion, Jamie B. Littleboy, Lisa Oyston, Thang M. Khuong, Qiao-Ping Wang, David T. Nguyen, Daniel Hesselson, Jamie E. Seymour and G. Gregory Neely ()
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Man-Tat Lau: The University of Sydney
John Manion: The University of Sydney
Jamie B. Littleboy: The University of Sydney
Lisa Oyston: The University of Sydney
Thang M. Khuong: The University of Sydney
Qiao-Ping Wang: The University of Sydney
David T. Nguyen: Garvan Institute of Medical Research
Daniel Hesselson: Garvan Institute of Medical Research
Jamie E. Seymour: James Cook University
G. Gregory Neely: The University of Sydney

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract The box jellyfish Chironex fleckeri is extremely venomous, and envenoming causes tissue necrosis, extreme pain and death within minutes after severe exposure. Despite rapid and potent venom action, basic mechanistic insight is lacking. Here we perform molecular dissection of a jellyfish venom-induced cell death pathway by screening for host components required for venom exposure-induced cell death using genome-scale lenti-CRISPR mutagenesis. We identify the peripheral membrane protein ATP2B1, a calcium transporting ATPase, as one host factor required for venom cytotoxicity. Targeting ATP2B1 prevents venom action and confers long lasting protection. Informatics analysis of host genes required for venom cytotoxicity reveal pathways not previously implicated in cell death. We also discover a venom antidote that functions up to 15 minutes after exposure and suppresses tissue necrosis and pain in mice. These results highlight the power of whole genome CRISPR screening to investigate venom mechanisms of action and to rapidly identify new medicines.

Date: 2019
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DOI: 10.1038/s41467-019-09681-1

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