Interpopulation venom variation has been widely documented in snakes across large geographical distances. This variability is known to markedly influence the effectiveness of snakebite therapy, as antivenoms manufactured against one population may not be effective against others. In contrast, the extent of intrapopulation venom variability, especially at finer geographical scales, remains largely uninvestigated. Moreover, given the historical focus on the 'big four' Indian snakes, our understanding of venom variation in medically important yet neglected snakes, such as the monocellate cobra (Naja kaouthia), remains unclear. To address this shortcoming, we investigated N. kaouthia venoms sampled across a small spatial scale (<50 km) in Eastern India. An interdisciplinary approach employed in this study unveiled considerable intrapopulation differences in the venom proteomic composition, pharmacological and biochemical activities, and toxicity profiles. Documentation of stark differences in venoms at such a finer geographical scale, despite the influence of similar ecological and environmental conditions, is intriguing. Furthermore, evaluation of in vitro and in vivo venom recognition and neutralisation potential of Indian polyvalent 'big four' antivenoms and Thai monovalent N. kaouthia antivenom revealed concerning deficiencies. These results highlight the negative impact of phylogenetic divergence and intrapopulation snake venom variation on the effectiveness of conventional antivenom therapy. SIGNIFICANCE: In contrast to our understanding of snake venom variation across large distances, which is theorised to be shaped by disparities in ecology and environment, intrapopulation variation at finer geographic scales remains scarcely investigated. Assessment of intrapopulation venom variability in Naja kaouthia at a small spatial scale (<50 km) in Eastern India unravelled considerable differences in venom compositions, activities and potencies. While the influence of subtle differences in prey preference and local adaptations cannot be ruled out, these findings, perhaps, also emphasise the role of accelerated molecular evolutionary regimes that rapidly introduce variations in evolutionarily younger lineages, such as advanced snakes. The inability of 'big four' Indian antivenoms and Thai N. kaouthia monovalent antivenom in countering these variations highlights the importance of phylogenetic considerations for the development of efficacious snakebite therapy. Thus, we provide valuable insights into the venoms of one of the most medically important yet neglected Indian snakes.
Keywords: Indian antivenoms; Intrapopulation venom variation; Naja kaouthia; Proteomics; Venomics.
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