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11 pages, 593 KiB

Open AccessArticle

Bothrops lanceolatus Envenoming in Martinique: A Historical Perspective of the Clinical Effectiveness of Bothrofav Antivenom Treatment

by Dabor Resiere, Jonathan Florentin, Hossein Mehdaoui, Hatem Kallel, Veronique Legris-Allusson, Papa Gueye and Remi Neviere

Toxins 2024, 16(3), 146; https://doi.org/10.3390/toxins16030146 - 13 Mar 2024

Viewed by 733

Abstract

Bothrofav, a monospecific antivenom, was introduced in June 1991 and has shown excellent effectiveness against life-threatening and thrombotic complications of Bothrops lanceolatus envenoming. Because of the reoccurrence of cerebral stroke events despite the timely administration of antivenom, new batches of Bothrofav were produced [...] Read more.

Bothrofav, a monospecific antivenom, was introduced in June 1991 and has shown excellent effectiveness against life-threatening and thrombotic complications of Bothrops lanceolatus envenoming. Because of the reoccurrence of cerebral stroke events despite the timely administration of antivenom, new batches of Bothrofav were produced and introduced into clinical use in January 2011. This study’s aim was to evaluate the effectiveness of Bothrofav generations at treating B. lanceolatus envenoming. During the first period of the study (2000–2010), 107 patients were treated with vials of antivenom produced in June 1991, while 282 envenomed patients were treated with vials of antivenom produced in January 2011 in the second study period (2011–2023). Despite timely antivenom administration, thrombotic complications reoccurred after an interval free of thrombotic events, and a timeframe analysis suggested that the clinical efficacy of Bothrofav declined after it reached its 10-year shelf-life. In of the case of an antivenom shortage due to the absence of regular batch production, no adverse effects were identified before the antivenom reached its 10-year shelf-life, which is beyond the accepted shelf-life for a liquid-formulation antivenom. While our study does not support the use of expired antivenom for potent, life-threatening B. lanceolatus envenoming, it can be a scientific message to public entities proving the necessity of new antivenom production for B. lanceolatus envenoming. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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19 pages, 3955 KiB

Open AccessArticle

De Novo Assembly of Venom Gland Transcriptome of Tropidolaemus wagleri (Temple Pit Viper, Malaysia) and Insights into the Origin of Its Major Toxin, Waglerin

by Choo Hock Tan, Kae Yi Tan and Nget Hong Tan

Toxins 2023, 15(9), 585; https://doi.org/10.3390/toxins15090585 - 21 Sep 2023

Viewed by 1362

Abstract

The venom proteome of Temple Pit Viper (Tropidolaemus wagleri) is unique among pit vipers, characterized by a high abundance of a neurotoxic peptide, waglerin. To further explore the genetic diversity of its toxins, the present study de novo assembled the venom [...] Read more.

The venom proteome of Temple Pit Viper (Tropidolaemus wagleri) is unique among pit vipers, characterized by a high abundance of a neurotoxic peptide, waglerin. To further explore the genetic diversity of its toxins, the present study de novo assembled the venom gland transcriptome of T. wagleri from west Malaysia. Among the 15 toxin gene families discovered, gene annotation and expression analysis reveal the dominating trend of bradykinin-potentiating peptide/angiotensin-converting enzyme inhibitor-C-type natriuretic peptide (BPP/ACEI-CNP, 76.19% of all-toxin transcription) in the transcriptome, followed by P-III snake venom metalloproteases (13.91%) and other toxins. The transcript TwBNP01 of BPP/ACEI-CNP represents a large precursor gene (209 amino acid residues) containing the coding region for waglerin (24 residues). TwBNP01 shows substantial sequence variations from the corresponding genes of its sister species, Tropidolaemus subannulatus of northern Philippines, and other viperid species which diversely code for proline-rich small peptides such as bradykinin-potentiating peptides (BPPs). The waglerin/waglerin-like peptides, BPPs and azemiopsin are proline-rich, evolving de novo from multiple highly diverged propeptide regions within the orthologous BPP/ACEI-CNP genes. Neofunctionalization of the peptides results in phylogenetic constraints consistent with a phenotypic dichotomy, where Tropidolaemus spp. and Azemiops feae convergently evolve a neurotoxic trait while vasoactive BPPs evolve only in other species. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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13 pages, 2895 KiB

Open AccessArticle

Increased Binding of von Willebrand Factor to Sub-Endothelial Collagen May Facilitate Thrombotic Events Complicating Bothrops lanceolatus Envenomation in Humans

by Olivier Pierre-Louis, Dabor Resiere, Celia Alphonsine, Fabienne Dantin, Rishika Banydeen, Marie-Daniela Dubois, Hossein Mehdaoui and Remi Neviere

Toxins 2023, 15(7), 441; https://doi.org/10.3390/toxins15070441 - 03 Jul 2023

Viewed by 1135

Abstract

Consumption coagulopathy and hemorrhagic syndrome exacerbated by blood anticoagulability remain the most important causes of lethality associated with Bothrops snake envenomation. Bothrops venom also engages platelet aggregation on the injured endothelium via von Willebrand factor (vWF) interactions. Besides platelet aggregation, some Bothrops venom [...] Read more.

Consumption coagulopathy and hemorrhagic syndrome exacerbated by blood anticoagulability remain the most important causes of lethality associated with Bothrops snake envenomation. Bothrops venom also engages platelet aggregation on the injured endothelium via von Willebrand factor (vWF) interactions. Besides platelet aggregation, some Bothrops venom toxins may induce qualitative thrombopathy, which has been in part related to the inhibition of vWF activation. We tested whether B. lanceolatus venom impaired vWF to collagen(s) binding (vWF:CB) activity. Experiments were performed with B. lanceolatus crude venom, in the presence or absence of Bothrofav, a monospecific B. lanceolatus antivenom. Venom of B. lanceolatus fully inhibited vWF to collagen type I and III binding, suggesting venom interactions with the vWF A3 domain. In contrast, B. lanceolatus venom increased vWF to collagen type VI binding, suggesting the enhancement of vWF binding to collagen at the vWF A1 domain. Hence, B. lanceolatus venom exhibited contrasting in vitro effects in terms of the adhesive properties of vWF to collagen. On the other hand, the antivenom Bothrofav reversed the inhibitory effects of B. lanceolatus venom on vWF collagen binding activity. In light of the respective distribution of collagen type III and collagen type VI in perivascular connective tissue and the sub-endothelium, a putative association between an increase in vWF:CB activity for collagen type VI and the onset of thrombotic events in human B. lanceolatus envenomation might be considered. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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30 pages, 7148 KiB

Open AccessArticle

De Novo Venom Gland Transcriptome Assembly and Characterization for Calloselasma rhodostoma (Kuhl, 1824), the Malayan Pit Viper from Malaysia: Unravelling Toxin Gene Diversity in a Medically Important Basal Crotaline

by Choo Hock Tan, Kae Yi Tan, Tzu Shan Ng, Nget Hong Tan and Ho Phin Chong

Toxins 2023, 15(5), 315; https://doi.org/10.3390/toxins15050315 - 29 Apr 2023

Cited by 1 | Viewed by 2221

Abstract

In Southeast Asia, the Malayan Pit Viper (Calloselasma rhodostoma) is a venomous snake species of medical importance and bioprospecting potential. To unveil the diversity of its toxin genes, this study de novo assembled and analyzed the venom gland transcriptome of C. [...] Read more.

In Southeast Asia, the Malayan Pit Viper (Calloselasma rhodostoma) is a venomous snake species of medical importance and bioprospecting potential. To unveil the diversity of its toxin genes, this study de novo assembled and analyzed the venom gland transcriptome of C. rhodostoma from Malaysia. The expression of toxin genes dominates the gland transcriptome by 53.78% of total transcript abundance (based on overall FPKM, Fragments Per Kilobase Million), in which 92 non-redundant transcripts belonging to 16 toxin families were identified. Snake venom metalloproteinase (SVMP, PI > PII > PIII) is the most dominant family (37.84% of all toxin FPKM), followed by phospholipase A₂ (29.02%), bradykinin/angiotensin-converting enzyme inhibitor-C-type natriuretic peptide (16.30%), C-type lectin (CTL, 10.01%), snake venom serine protease (SVSP, 2.81%), L-amino acid oxidase (2.25%), and others (1.78%). The expressions of SVMP, CTL, and SVSP correlate with hemorrhagic, anti-platelet, and coagulopathic effects in envenoming. The SVMP metalloproteinase domains encode hemorrhagins (kistomin and rhodostoxin), while disintegrin (rhodostomin from P-II) acts by inhibiting platelet aggregation. CTL gene homologues uncovered include rhodocytin (platelet aggregators) and rhodocetin (platelet inhibitors), which contribute to thrombocytopenia and platelet dysfunction. The major SVSP is a thrombin-like enzyme (an ancrod homolog) responsible for defibrination in consumptive coagulopathy. The findings provide insight into the venom complexity of C. rhodostoma and the pathophysiology of envenoming. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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24 pages, 7277 KiB

Open AccessArticle

Exploring Toxin Genes of Myanmar Russell’s Viper, Daboia siamensis, through De Novo Venom Gland Transcriptomics

by Khin Than Yee, Jason Macrander, Olga Vasieva and Ponlapat Rojnuckarin

Toxins 2023, 15(5), 309; https://doi.org/10.3390/toxins15050309 - 26 Apr 2023

Cited by 1 | Viewed by 1842

Abstract

The Russell’s viper (Daboia siamensis) is a medically important venomous snake in Myanmar. Next-generation sequencing (NGS) shows potential to investigate the venom complexity, giving deeper insights into snakebite pathogenesis and possible drug discoveries. mRNA from venom gland tissue was extracted and [...] Read more.

The Russell’s viper (Daboia siamensis) is a medically important venomous snake in Myanmar. Next-generation sequencing (NGS) shows potential to investigate the venom complexity, giving deeper insights into snakebite pathogenesis and possible drug discoveries. mRNA from venom gland tissue was extracted and sequenced on the Illumina HiSeq platform and de novo assembled by Trinity. The candidate toxin genes were identified via the Venomix pipeline. Protein sequences of identified toxin candidates were compared with the previously described venom proteins using Clustal Omega to assess the positional homology among candidates. Candidate venom transcripts were classified into 23 toxin gene families including 53 unique full-length transcripts. C-type lectins (CTLs) were the most highly expressed, followed by Kunitz-type serine protease inhibitors, disintegrins and Bradykinin potentiating peptide/C-type natriuretic peptide (BPP-CNP) precursors. Phospholipase A₂, snake venom serine proteases, metalloproteinases, vascular endothelial growth factors, L-amino acid oxidases and cysteine-rich secretory proteins were under-represented within the transcriptomes. Several isoforms of transcripts which had not been previously reported in this species were discovered and described. Myanmar Russell’s viper venom glands displayed unique sex-specific transcriptome profiles which were correlated with clinical manifestation of envenoming. Our results show that NGS is a useful tool to comprehensively examine understudied venomous snakes. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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22 pages, 12447 KiB

Open AccessArticle

Anti-Metalloproteases: Production and Characterization of Polyclonal IgG Anti-F2 Fraction Antibodies Purified from the Venom of the Snake Bitis arietans

by Kemily Stephanie de Godoi, Felipe Raimondi Guidolin, Fernanda Calheta Vieira Portaro, Patrick Jack Spencer and Wilmar Dias da Silva

Toxins 2023, 15(4), 264; https://doi.org/10.3390/toxins15040264 - 01 Apr 2023

Cited by 2 | Viewed by 1422

Abstract

Bitis arietans is a medically important snake found in Sub-Saharan Africa. The envenomation is characterized by local and systemic effects, and the lack of antivenoms aggravates the treatment. This study aimed to identify venom toxins and develop antitoxins. The F2 fraction obtained from [...] Read more.

Bitis arietans is a medically important snake found in Sub-Saharan Africa. The envenomation is characterized by local and systemic effects, and the lack of antivenoms aggravates the treatment. This study aimed to identify venom toxins and develop antitoxins. The F2 fraction obtained from Bitis arietans venom (BaV) demonstrated the presence of several proteins in its composition, including metalloproteases. Titration assays carried out together with the immunization of mice demonstrated the development of anti-F2 fraction antibodies by the animals. The determination of the affinity of antibodies against different Bitis venoms was evaluated, revealing that only BaV had peptides recognized by anti-F2 fraction antibodies. In vivo analyses demonstrated the hemorrhagic capacity of the venom and the effectiveness of the antibodies in inhibiting up to 80% of the hemorrhage and 0% of the lethality caused by BaV. Together, the data indicate: (1) the prevalence of proteins that influence hemostasis and envenomation; (2) the effectiveness of antibodies in inhibiting specific activities of BaV; and (3) isolation and characterization of toxins can become crucial steps in the development of new alternative treatments. Thus, the results obtained help in understanding the envenoming mechanism and may be useful for the study of new complementary therapies. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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22 pages, 2138 KiB

Open AccessArticle

Snake Venomics and Antivenomics of Cape Cobra (Naja nivea) from South Africa: Insights into Venom Toxicity and Cross-Neutralization Activity

by Choo Hock Tan, Kin Ying Wong, Li-Kun Huang, Kae Yi Tan, Nget Hong Tan and Wen-Guey Wu

Toxins 2022, 14(12), 860; https://doi.org/10.3390/toxins14120860 - 07 Dec 2022

Cited by 5 | Viewed by 2552

Abstract

Naja nivea (Cape Cobra) is endemic to southern Africa. Envenoming by N. nivea is neurotoxic, resulting in fatal paralysis. Its venom composition, however, has not been studied in depth, and specific antivenoms against it remain limited in supply. Applying a protein decomplexation approach, [...] Read more.

Naja nivea (Cape Cobra) is endemic to southern Africa. Envenoming by N. nivea is neurotoxic, resulting in fatal paralysis. Its venom composition, however, has not been studied in depth, and specific antivenoms against it remain limited in supply. Applying a protein decomplexation approach, this study unveiled the venom proteome of N. nivea from South Africa. The major components in the venom are cytotoxins/cardiotoxins (~75.6% of total venom proteins) and alpha-neurotoxins (~7.4%), which belong to the three-finger toxin family. Intriguingly, phospholipase A₂ (PLA₂) was undetected—this is a unique venom phenotype increasingly recognized in the African cobras of the Uraeus subgenus. The work further showed that VINS African Polyvalent Antivenom (VAPAV) exhibited cross-reactivity toward the venom and immunorecognized its toxin fractions. In mice, VAPAV was moderately efficacious in cross-neutralizing the venom lethality with a potency of 0.51 mg/mL (amount of venom completely neutralized per milliliter of antivenom). In the challenge-rescue model, VAPAV prevented death in 75% of experimentally envenomed mice, with slow recovery from neurotoxicity up to 24 h. The finding suggests the potential para-specific utility of VAPAV for N. nivea envenoming, although a higher dose or repeated administration of the antivenom may be required to fully reverse the neurotoxic effect of the venom. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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Review

Jump to: Research

17 pages, 2822 KiB

Open AccessReview

Toxic Habits: An Analysis of General Trends and Biases in Snake Venom Research

by Ignazio Avella, Wolfgang Wüster, Luca Luiselli and Fernando Martínez-Freiría

Toxins 2022, 14(12), 884; https://doi.org/10.3390/toxins14120884 - 17 Dec 2022

Cited by 5 | Viewed by 2947

Abstract

Biases in snake venom research have been partially identified but seldomly quantified. Using the Google Scholar web search engine, we collected a total of 267 articles published between 1964 and 2021, and reviewed them to assess the main trends in this field of [...] Read more.

Biases in snake venom research have been partially identified but seldomly quantified. Using the Google Scholar web search engine, we collected a total of 267 articles published between 1964 and 2021, and reviewed them to assess the main trends in this field of study. We developed a 4-category classification of the harmful potential of each of the 298 snake species retrieved from the analysed publications, and tested whether taxonomy, realm of origin, and/or assigned hazard category could affect how often each of them appeared in the articles considered. Overall, viperids were significantly more represented than any other snake taxon retrieved. The Neotropics were the most represented biogeographic realm for number of studied species, whereas information about the country of origin of the analysed specimens was often incomplete. The vast majority of the publications focused on snake venom characterisation, whereas more ecology-related topics were rarely considered. Hazard category and biogeographic realm of origin of each species had a significant effect on the number of articles dedicated to it, suggesting that a snake’s harmful potential and place of origin influence its popularity in venom studies. Our analysis showed an overall positive trend in the number of snake venom studies published yearly, but also underlined severe neglect of snake families of supposedly minor medical relevance (e.g., Atractaspididae), underrepresentation of some of the areas most impacted by snakebite (i.e., Indomalayan and Afrotropic realms), and limited interest in the ecological and functional context of snake venom. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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