Defining the pathogenic threat of envenoming by South African shield-nosed and coral snakes (genus Aspidelaps), and revealing the likely efficacy of available antivenom

Abstract

Defining the pathogenic threat of envenoming by south african shield-nosed and coral snakes (genus aspidelaps), and revealing the likely efficacy of available antivenom. Jprot (2018), 1 Defining the pathogenic threat of envenoming by south african shield-nosed and coral snakes (genus aspidelaps), and revealing the likely efficacy of available antivenom ABSTRACT While envenoming by the southern African shield-nosed or coral snakes (genus Aspidelaps) has caused fatalities, bites are uncommon. Consequently, this venom is not used in the mixture of snake venoms used to immunise horses for the manufacture of regional SAIMR (South African Institute for Medical Research) polyvalent antivenom.Aspidelaps species are even excluded from the manufacturer's list of venomous snakes that can be treated by this highly effective product. This leaves clinicians, albeit rarely, in a therapeutic vacuum when treating envenoming by these snakes. This is a significantly understudied small group of nocturnal snakes and little is known about their venom compositions and toxicities. Using a murine preclinical model, this study determined that the paralysing toxicity of venoms from Aspidelaps scutatus intermedius, A. lubricus cowlesi and A. l. lubricus approached that of venoms from highly neurotoxic African cobras and mambas. This finding was consistent with the cross-genus dominance of venom three-finger toxins, including numerous isoforms which showed extensive interspecific variation. Our comprehensive analysis of venom proteomes showed that the three Aspidelaps species possess highly similar venom proteomic compositions. We also revealed that the SAIMR polyvalent antivenom crossreacted extensively in vitro with venom proteins of the three Aspidelaps. Importantly, this cross-genus venom-IgG binding translated to preclinical (in a murine model) neutralisation of A. s. intermedius venom-induced lethality by the SAIMR polyvalent antivenom, at doses comparable with those that neutralise venom from the cape cobra (Naja nivea), which the antivenom is directed against. Our results suggest a wider than anticipated clinical utility of the SAIMR polyvalent antivenom, and here we seek to inform southern African clinicians that this readily available antivenom is likely to prove effective for victims of Aspidelaps envenoming.

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

“…Consequently, venom toxicity/pathology analyses in combination with venom proteomics, antivenomics, and/or immunological analyses have been integrated to investigate the paraspecificity of antivenoms (Calvete et al, 2009;Madrigal et al, 2012;Pla et al, 2013;Tan et al, 2015). Such studies have revealed surprising cross-reactivity of antivenoms against distinct, non-targeted, snake species, such as: (i) the potential utility of Asian antivenoms developed against terrestrial elapid snakes at neutralizing the venom toxicity of potent sea snake venoms (Tan et al, 2015), (ii) the seeming utility of African polyvalent antivenom at neutralizing the venom of a genus of elapid snakes not including in the immunizing mixture (Whiteley et al, 2019), and (iii) the potential for saw-scaled viper antivenom to be used as an alternative treatment for bites by the boomslang (Dispholidus typus) in regions where the appropriate speciesspecific antivenom is unavailable or unaffordable (Ainsworth et al, 2018). The later of these studies demonstrated crossneutralization between distinct snake lineages (e.g., viper and colubrid), and this surprising finding was ultimately informed by venom comparisons indicating that these snakes had converged upon similar toxin compositions.…”

An analysis of preclinical efficacy testing of antivenoms for sub-Saharan Africa: Inadequate independent scrutiny and poor-quality reporting are barriers to improving snakebite treatment and management

“…Similar ED 50 values were reported for Antivipmyn-Africa, VACSERA and Fav-Afrique antivenoms against the venom of the forest cobra, N. melanoleuca (1778.8-2777.8 μl/mg) (Fig 2B, S1 Table) [5,38,40]. Two of three antivenoms (Antivipmyn-Africa and SAIMR Polyvalent) tested against N. nivea (cape cobra) venom, demonstrated efficacy in preventing venom-induced lethality in mice, although SAIMR Polyvalent was four times more efficacious (2115.2 vs. 529.9 μl/mg, respectively) [5,42] (Fig 2B, S1 Table). The…”

Modeling Vertebrate Adult Stem Cells and Their Progeny

“…We also detected expression of cysteine-rich secretory proteins (CRISP), snake venom metalloproteinases (SVMP) and kunitz type protease inhibitors (KUN) (Figure 2E and S1G). The relative abundance of these toxin classes matched the venom gland tissue at transcriptome level, and the crude venom composition at protein level (Whiteley et al, 2019) (Figure 2E). Of note, the seven-day differentiation protocol increased overall toxin gene expression but reduced the expression of CRISP (Figure 2D and E).…”

“…Organoid cluster 3 consisted of cells co-expressing C-type lectin (CTL) and Waprin-related toxins ( Figure S3E) (Torres et al, 2003;Ogawa et al, 2005). CTLs have not previously been detected in the Aspidelaps lubricus venom proteome and did not form an independent cluster in the tissue dataset (Whiteley et al, 2019). Cluster 5, containing cells exclusively derived from differentiated organoids, was devoid of any known toxin expression.…”

“…Highlighted are highly expressed toxin classes (3FTX,KUN, SVMP, CRISP), as well as liver and pancreas markers. (E) Contribution of toxin-encoding genes (orange) and non-toxin genes (grey) to the transcriptome per sample, and the contribution of toxin classes in expansion medium and differentiation medium compared to venom gland tissue mRNA and venom proteome (*dataset fromWhiteley and Casewell et al, 2019) (3FTx = three-finger toxin, CRISP = cysteine-rich secretory protein, SVMP = snake venom metalloproteinase, Kunitz = Kunitz trypsin inhibitor, others include cobra venom factor (CVF), L-amino acid oxidase (LAOO) and phosphodiesterases (PDE)) (See alsoFigure S1G).…”