Dissecting Daboia: Investigating synergistic effects of Russell's viper venom toxins

Snakebite envenomation remains a life-threatening public health challenge in developing regions of the world. In India, Russell's viper (Daboia russelii) is responsible for the highest number of snakebite-inflicted mortality and morbidity. Diverse toxins have been reported in D. russelii venoms. However, the precise role of these toxins and whether they function independently, additively or synergistically remains unclear. To bridge this knowledge gap, we resolved D. russelii venom into distinct fractions containing major toxins and subjected them to various in vitro and in vivo experiments. Our findings suggest that combinations of fractions exhibit considerably higher toxicity than individual fractions. For example, a combination of certain SVMP- and PLA₂-rich fractions was more cytotoxic and haemorrhagic than the respective fractions. Furthermore, this combination was more potent than other fractions or their combinations in experimental animals. We highlight, for the first time, a synergy between D. russelii venom SVMP and PLA₂. We were able to demonstrate that specifically inhibiting either of these toxins and disrupting the synergy can effectively neutralise the deleterious effects of D. russelii venom. Our findings emphasise the role of toxin synergy in enhancing venom potency and highlight the importance of understanding synergism in effectively mitigating snakebite pathology.