Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote
Autor: | Thang M. Khuong, Man-Tat Lau, John Manion, Daniel Hesselson, G. Gregory Neely, Lisa J. Oyston, Qiao-Ping Wang, Jamie Seymour, Jamie B. Littleboy, David T. Nguyen |
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Rok vydání: | 2019 |
Předmět: |
Cell death
Male 0301 basic medicine Programmed cell death Jellyfish Cell Survival Science Antidotes Blotting Western General Physics and Astronomy Poison control Venom 02 engineering and technology Pharmacology complex mixtures Article General Biochemistry Genetics and Molecular Biology Mice Necrosis 03 medical and health sciences Cnidarian Venoms Chironex fleckeri biology.animal Box jellyfish Animals lcsh:Science Cytotoxicity Cumulus Cells Multidisciplinary biology Drug discovery General Chemistry 021001 nanoscience & nanotechnology biology.organism_classification Sphingomyelins 3. Good health Mechanisms of disease Gene Ontology 030104 developmental biology Calcium transporting ATPase Cubozoa Calcium lcsh:Q 0210 nano-technology |
Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) Nature Communications |
ISSN: | 2041-1723 |
Popis: | 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. Box jellyfish venom causes tissue damage, pain, and death through unknown molecular mechanisms. Here, Lau et al. perform a CRISPR screen to identify genes required for venom action and use this information to develop an antidote that blocks venom-induced pain and tissue damage in vivo. |
Databáze: | OpenAIRE |
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