The medical threat of mamba envenoming in sub-Saharan Africa revealed by genus-wide analysis of venom composition, toxicity and antivenomics profiling of available antivenoms

Abstract

The mambas (genus Dendroaspis) comprise five especially notorious medically important venomous snakes endemic to sub-Saharan Africa. Their highly potent venoms comprise a high diversity of pharmacologically active peptides, including extremely rapid-acting neurotoxins. Previous studies on mamba venoms have focused on the biochemical and pharmacological characterisation of their most relevant toxins to rationalize the common neurological and neuromuscular symptoms of envenomings caused by these species, but there has been little work on overall venom composition or comparisons between them. Only very recently an overview of the composition of the venom of two Dendroaspis species, D. angusticeps and D. polylepis, has been unveiled through venomics approaches. Here we present the first genus-wide transcriptomic-proteomic analysis of mamba venom composition. The transcriptomic analyses described in this paper have contributed 29 (D. polylepis), 23 (D. angusticeps), 40 (D. viridis), 25 (D. j. jamesoni) and 21 (D. j. kaimosae), novel full-length toxin sequences to the non-redundant Dendroaspis sequence database. The mamba genus-wide venomic analysis demonstrated that major D. polylepis venom components are Kunitz-fold family toxins. This feature is unique in relation to the relatively conserved three-finger toxin (3FTx)-dominated venom compositions of the green mambas. Venom variation was interpreted in the context of dietary variation due to the divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas. Additionally, the degree of cross-reactivity conservation of mamba venoms was assessed by antivenomics against a panel of commercial antivenoms generated for the sub-Saharan Africa market. This study provides a genus-wide overview to infer which available antivenoms may be capable of neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the pharmacological profiles of mamba venoms at locus resolution. This understanding will contribute to the generation of a safer and more efficacious pan-Dendroaspis therapeutic antivenom against any mamba envenomation.

Mechanisms Responsible for the Anticoagulant Properties of Neurotoxic Dendroaspis Venoms: A Viscoelastic Analysis

“…Dendroaspis polylepis [13,14] 31.0-45.1 48.9-61.1 1.8-3.2 Dendroaspis angusticeps [13,15] 69.2-71. 4 14.5-16.…”

“…4 14.5-16. 3 3.4-6.7 Dendroaspis jamesoni [13] 80. 3 15.1 0.5 Dendroaspis viridis [13] 77.7 15.2 2.7…”

“…Recent characterizations of the proteome of venom obtained from the four species of Dendroaspis [13-15] offered differences that could potentially explain these anticoagulant potency differences [11,12]. As displayed in Table 1, unlike most venoms derived from Elapidae snakes, Dendroaspis venoms are predominantly composed of non-enzymatic neurotoxins such as 3-finger toxins (3-FTx) and Kunitz-type serine protease inhibitors (Kunitz-type SPI), with metalloproteinases (SVMPs) comprising less than 7% [13][14][15] and PLA 2 comprising from zero to less than 0.15% [13] of the proteomes. As D. polylepis venom has a greater amount of Kunitz-type SPI than 3-FTx compared to the other three species, and given that isolated 3-FTx have acted as plasmatic anticoagulants [16,17], perhaps the predominance of 3-FTx in the other mamba species' venom that was tested could explain the differences in anticoagulant potency [11,12].…”

A perspective view of top‐down proteomics in snake venom research

“…The results revealed previously undetected proteoforms and also the site of acetylation of lysine residues in a number of venom protein species. To further employ the power of the venomics strategy, Ainsworth et al extended the previous study by transcriptomic‐proteomic analysis of other species of genus Dendroaspis on the locus‐resolution level. This mamba genus‐wide venomics analysis exhibited intrageneric venom variability in precise detail which was then used to assess the immunological profile of the African black and green mamba venoms against seven commercial antivenoms via second‐generation snake antivenomics .…”

Extended snake venomics by top-down in-source decay: Investigating the newly discovered Anatolian Meadow viper subspecies, Vipera anatolica senliki

“…10–13 In this context, the recently introduced top-down protocol for snake venoms provide remedy by directly analyzing intact proteins and peptides out of crude venoms using high-resolution tandem mass spectrometry. 14–17 However, in case of higher molecular weight compounds (>30 kDa), which are typically strongly represented in the genus of Viperidae , the top-down analysis only provides a partial characterization and is still challenging. 18–21…”