Journal
PLOS NEGLECTED TROPICAL DISEASES
Volume 12, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pntd.0006427
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Funding
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - CAPES [Toxinologia 23038000825/2011-63]
- Fundacao de Amparo a Pesquisa do Estado de Minas Gerais - FAPEMIG Fundacao de Amparo a Pesquisa do Estado de Minas Gerais - FAPEMIG ] [APQ 08831-15]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq [PVE 71/2013, 407266/2013-5]
- Wellcome Trust Pathfinder grant [201054/Z/16/Z]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq [Science Without Borders] [4803318142983356]
- Newton Fund [MRC-CONFAP] [MR/M026310/1]
- MRC [MR/M026310/1] Funding Source: UKRI
- Wellcome Trust [201054/Z/16/Z] Funding Source: Wellcome Trust
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Envenomation by the bushmaster snake Lachesis muta muta is considered severe, characterized by local effects including necrosis, the main cause of permanent disability. However, cellular mechanisms related to cell death and tissue destruction, triggered by snake venoms, are poorly explored. The purpose of this study was to investigate the cytotoxic effect caused by L. m. muta venom in normal human keratinocytes and to identify the cellular processes involved in in cellulo envenomation. In order to investigate venom effect on different cell types, Alamar Blue assay was performed to quantify levels of cellular metabolism as a readout of cell viability. Apoptosis, necrosis and changes in mitochondrial membrane potential were evaluated by flow cytometry, while induction of autophagy was assessed by expression of GFP-LC3 and analyzed using fluorescence microscopy. The cytotoxic potential of the venom is shown by reduced cell viability in a concentration-dependent manner. It was also observed the sequential appearance of cells undergoing autophagy (by 6 hours), apoptosis and necrosis (12 and 24 hours). Morphologically, incubation with L. m. muta venom led to a significant cellular retraction and formation of cellular aggregates. These results indicate that L. m. muta venom is cytotoxic to normal human keratinocytes and other cell lines, and this toxicity involves the integration of distinct modes of cell death. Autophagy as a cell death mechanism, in addition to apoptosis and necrosis, can help to unravel cellular pathways and mechanisms triggered by the venom. Understanding the mechanisms that underlie cellular damage and tissue destruction will be useful in the development of alternative therapies against snakebites.
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