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Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib. / Bartlett, Keirah E; Hall, Steve; Rasmussen, Sean A et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 121, No. 19, e2315597121, 07.05.2024, p. 1-12.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Bartlett, KE, Hall, S, Rasmussen, SA, Crittenden, E, Dawson, CA, Albulescu, L-O, Laprade, W, Harrison, RA, Saviola, AJ, Modahl, C, Jenkins, TP, Wilkinson, MC, Gutiérrez, JM & Casewell, NR 2024, 'Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib', Proceedings of the National Academy of Sciences of the United States of America, vol. 121, no. 19, e2315597121, pp. 1-12. https://doi.org/10.1073/pnas.2315597121

APA

Bartlett, K. E., Hall, S., Rasmussen, S. A., Crittenden, E., Dawson, C. A., Albulescu, L.-O., Laprade, W., Harrison, R. A., Saviola, A. J., Modahl, C., Jenkins, T. P., Wilkinson, M. C., Gutiérrez, J. M., & Casewell, N. R. (2024). Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib. Proceedings of the National Academy of Sciences of the United States of America, 121(19), 1-12. Article e2315597121. https://doi.org/10.1073/pnas.2315597121

Vancouver

Bartlett KE, Hall S, Rasmussen SA, Crittenden E, Dawson CA, Albulescu LO et al. Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib. Proceedings of the National Academy of Sciences of the United States of America. 2024 May 7;121(19):1-12. e2315597121. Epub 2024 Apr 30. doi: 10.1073/pnas.2315597121

Author

Bartlett, Keirah E ; Hall, Steve ; Rasmussen, Sean A et al. / Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib. In: Proceedings of the National Academy of Sciences of the United States of America. 2024 ; Vol. 121, No. 19. pp. 1-12.

Bibtex

@article{1d29105b0d6b4c9d9b173a5ace87d6a1,
title = "Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib",
abstract = "Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the aetiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a new therapeutic strategy to more effectively prevent life-changing morbidity caused by snakebite in rural Africa.",
keywords = "snakebite",
author = "Bartlett, {Keirah E} and Steve Hall and Rasmussen, {Sean A} and Edouard Crittenden and Dawson, {Charlotte A} and Laura-Oana Albulescu and William Laprade and Harrison, {Robert A} and Saviola, {Anthony J} and Cassandra Modahl and Jenkins, {Timothy P.} and Wilkinson, {Mark C.} and Guti{\'e}rrez, {Jos{\'e} Mar{\'i}a} and Casewell, {Nicholas R.}",
year = "2024",
month = may,
day = "7",
doi = "10.1073/pnas.2315597121",
language = "English",
volume = "121",
pages = "1--12",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "19",

}

RIS

TY - JOUR

T1 - Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib

AU - Bartlett, Keirah E

AU - Hall, Steve

AU - Rasmussen, Sean A

AU - Crittenden, Edouard

AU - Dawson, Charlotte A

AU - Albulescu, Laura-Oana

AU - Laprade, William

AU - Harrison, Robert A

AU - Saviola, Anthony J

AU - Modahl, Cassandra

AU - Jenkins, Timothy P.

AU - Wilkinson, Mark C.

AU - Gutiérrez, José María

AU - Casewell, Nicholas R.

PY - 2024/5/7

Y1 - 2024/5/7

N2 - Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the aetiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a new therapeutic strategy to more effectively prevent life-changing morbidity caused by snakebite in rural Africa.

AB - Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the aetiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a new therapeutic strategy to more effectively prevent life-changing morbidity caused by snakebite in rural Africa.

KW - snakebite

U2 - 10.1073/pnas.2315597121

DO - 10.1073/pnas.2315597121

M3 - Journal article

VL - 121

SP - 1

EP - 12

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 19

M1 - e2315597121

ER -