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

Lau, Man-Tat, Manion, John, Littleboy, Jamie B., Oyston, Lisa, Khuong, Thang M., Wang, Qiao-Ping, Nguyen, David T., Hesselson, Daniel, Seymour, Jamie E., and Neely, G. Gregory (2019) Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote. Nature Communications, 10. 1655.

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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.

Item ID: 58219
Item Type: Article (Research - C1)
ISSN: 2041-1723
Keywords: venom; toxicity; cytotoxicity; antidote; Chironex fleckeri; box jellyfish
Copyright Information: © The Author(s) 2019. Open Access: this article is licensed under a Creative Commons Attribution 4.0 International License.
Funders: Cancer Institute NSW (CI), Cancer Council NSW (CC), National Health and Medical Research Council (NHMRC)
Date Deposited: 26 Sep 2019 02:29
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110101 Medical Biochemistry: Amino Acids and Metabolites @ 100%
SEO Codes: 92 HEALTH > 9204 Public Health (excl. Specific Population Health) > 920499 Public Health (excl. Specific Population Health) not elsewhere classified @ 100%
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