Innovative Immunization Strategies for Antivenom Development

Bermúdez-Méndez, Erick; Fuglsang-Madsen, Albert; Føns, Sofie; Lomonte, Bruno; Gutiérrez, José Marı́a; Laustsen, Andreas Hougaard

doi:10.3390/toxins10110452

Cited by 61 publications

(46 citation statements)

References 222 publications

(342 reference statements)

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“…Much of our current understanding of snake venom is based on proteomic studies that have provided only a partial picture of its components [69][70][71] . A comprehensive catalog of venom proteins, their expression and coding sequence is fundamental to developing a safe and effective antivenom 15,72 . Also, such a detailed catalog of venom components will be valuable for drug candidate prospecting.…”

Section: Discussionmentioning

confidence: 99%

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The Indian cobra reference genome and transcriptome enables comprehensive identification of venom toxins

Suryamohan¹,

Krishnankutty

Guillory³

et al. 2020

Nat Genet

139

136

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ossil remains from ~100 million years ago (Ma) show that snakes were widely distributed across the world by the late Cretaceous period 1. During the course of their evolution, snakes lost their limbs, acquiring a serpentine body 2. Some also evolved or co-opted venom systems to help subdue, capture and digest their prey 2,3. The Colubroides clade of advanced snakes encompasses >3,000 extant species including >600 venomous species 4. The most venomous snakes include the true vipers and pit vipers, both members of the Viperidae family, and cobras, kraits, mambas and sea snakes from the Elapidae family 5. Although humans are not an intended target, accidental contact with venomous snakes can be deadly. Snakebite envenoming is a serious neglected tropical disease that affects ~5 million people worldwide annually, leading to ~400,000 amputations and >100,000 deaths 6. In India alone, the high rural population density combined with the presence of the 'big four' deadly snakes, namely the Indian cobra (Naja naja), Russell's viper (Daboia russelli), sawscaled viper (Echis carinatus) and common krait (Bungarus caeruleus), results in >46,000 snakebite-related deaths annually 7. Snake venom is a potent lethal cocktail rich in proteins and peptides, secreted by specialized venom gland cells. Venom components can be broadly classified as neurotoxic, cytotoxic, cardiotoxic or hemotoxic, and the composition can vary both between and within species 8-11. Currently, snake antivenom is the only treatment effective in the prevention or reversal of the effects of envenomation. Since 1896, antivenom has been developed by immunization of large mammals, such as the horse, with snake venom to generate a cocktail of antibodies that are used for therapy 12. Given the heterologous nature of these antibodies, they often elicit adverse immunological responses when treating snakebite victims 13. Moreover, the antivenom composition is not well defined and its ability to neutralize the venom

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Section: Discussionmentioning

confidence: 99%

“…This is further exacerbated by the lack of access to antivenom and its high cost in many developing countries 14 . Although several alternative approaches have been proposed, large animal-based antivenom production using extracted snake venom as the antigen continues to be the standard practice [15][16][17][18] .…”

Section: Nature Geneticsmentioning

confidence: 99%

The Indian cobra reference genome and transcriptome enables comprehensive identification of venom toxins

Suryamohan¹,

Krishnankutty

Guillory³

et al. 2020

Nat Genet

139

136

View full text Add to dashboard Cite

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“…Given our finding that FNAV is, at best, only partially effective in controlling the local necrotic damage induced by N. atra venom, it is important to develop novel therapeutic interventions for treating N. atra envenomation in Taiwan. Several advanced biotechnological tools have recently been adopted for developing alternative strategies for antivenom production [53,54]. Applying expertise in synthetic biology, antibody research and immunology, a number of researchers have attempted to develop recombinant antivenoms and investigate their ability to neutralize toxins from snake venom [55][56][57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of local necrosis induced by Naja atra venom: Assessment of the neutralization ability of Taiwanese freeze-dried neurotoxic antivenom in animal models

et al. 2020

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Naja atra envenomation is one of the most significant clinical snakebite concerns in Taiwan. Taiwanese freeze-dried neurotoxic antivenom (FNAV) is currently used clinically for the treatment of cobra snakebite, and has been shown to limit the mortality of cobra envenomation to less than 1%. However, more than half of victims (60%) require surgery because of local tissue necrosis, a major problem in patients with cobra envenomation. Although the importance of evaluating the neutralizing effect of FNAV on this pathology is recognized, whether FNAV is able to prevent the local necrosis extension induced by N. atra venom has not been investigated in detail. Cytotoxins (CTXs) are considered as the major components of N. atra venom that cause necrosis. In the current study, we isolated CTXs from whole cobra venom and used both whole venom and purified CTXs to develop animal models for assessing the neutralization potential of FNAV against venom necrotizing activity. Local necrotic lesions were successfully produced in mice using CTXs in place of whole N. atra venom. FNAV was able to rescue mice from a subcutaneously injected lethal dose of cobra venom; however, it was unable to prevent CTX-induced dermo-necrosis. Furthermore, using the minimal necrosis dose (MND) of CTXs and venom proteome data, we found a dose of whole N. atra venom suitable for FNAV and developed a workable protocol for inducing local necrosis in rodent models that successfully imitated the clinical circumstance of cobra envenoming. This information provides a more comprehensive understanding of PLOS Neglected Tropical Diseases | https://doi.the pathophysiology of N. atra envenomation, and serves as a guide for improving current antivenom strategies and advancing clinical snakebite management in Taiwan. Author summaryNaja atra envenomation is an important public health issue in Taiwan. Although the mortality rate of cobra snakebite is controlled using antivenom, more than half of victims develop symptoms of local necrosis and require surgical intervention. Whether the Taiwanese freeze-dried neurotoxic antivenom (FNAV) currently in clinical use is able to prevent the local necrosis extension induced by N. atra venom is still unclear. In this study, we developed a dermo-necrosis animal model using purified cytotoxins (CTXs), the major necrosis-related proteins from N. atra venom. We found that FNAV was able to neutralize the lethality of whole cobra venom, but was unable to neutralize the necrosis induced by CTXs in vivo. This finding introduced an example that supplementary quality control assays may be necessary to determine the effectiveness of antivenoms in neutralizing specific pathology induced by the venom; only evaluating the rodent lethality prevention is insufficient. Our results provide insights that should help improve current antivenoms and advance cobra snakebite management in Taiwan.Pathogenesis of local necrosis induced by Naja atra venom PLOS Neglected Tropical Diseases | https://doi.org/10.The lyophilized fractions from RP-HPLC were d...

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“…These molecules and strategies could be used to improve the specific treatment of loxoscelism, mitigating the suffering caused in several regions of the world where these accidents are endemic and recurrent. The use of recombinant forms of loxoscelic PLDs or synthetic peptides mimicking sequences of these enzymes was already considered an effective strategy in the generation of sera with high antibody titers, high neutralization capacity and therapeutic potential [108]. It is important to mention that these initiatives would not alter the production lines of conventional sera.…”

Section: A New Generation Of Anti-loxoscelic Sera and Vaccines Using mentioning

confidence: 99%

Forty Years of the Description of Brown Spider Venom Phospholipases-D

Gremski

Justa

Silva

et al. 2020

Toxins

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Spiders of the genus Loxosceles, popularly known as Brown spiders, are considered a serious public health issue, especially in regions of hot or temperate climates, such as parts of North and South America. Although the venoms of these arachnids are complex in molecular composition, often containing proteins with distinct biochemical characteristics, the literature has primarily described a family of toxins, the Phospholipases-D (PLDs), which are highly conserved in all Loxosceles species. PLDs trigger most of the major clinical symptoms of loxoscelism i.e., dermonecrosis, thrombocytopenia, hemolysis, and acute renal failure. The key role played by PLDs in the symptomatology of loxoscelism was first described 40 years ago, when researches purified a hemolytic toxin that cleaved sphingomyelin and generated choline, and was referred to as a Sphingomyelinase-D, which was subsequently changed to Phospholipase-D when it was demonstrated that the enzyme also cleaved other cellular phospholipids. In this review, we present the information gleaned over the last 40 years about PLDs from Loxosceles venoms especially with regard to the production and characterization of recombinant isoforms. The history of obtaining these toxins is discussed, as well as their molecular organization and mechanisms of interaction with their substrates. We will address cellular biology aspects of these toxins and how they can be used in the development of drugs to address inflammatory processes and loxoscelism. Present and future aspects of loxoscelism diagnosis will be discussed, as well as their biotechnological applications and actions expected for the future in this field.

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Innovative Immunization Strategies for Antivenom Development

Cited by 61 publications

References 222 publications

The Indian cobra reference genome and transcriptome enables comprehensive identification of venom toxins

The Indian cobra reference genome and transcriptome enables comprehensive identification of venom toxins

Pathogenesis of local necrosis induced by Naja atra venom: Assessment of the neutralization ability of Taiwanese freeze-dried neurotoxic antivenom in animal models

Forty Years of the Description of Brown Spider Venom Phospholipases-D

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