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Antivenomics As a Tool to Improve the Neutralizing Capacity of the Crotalic

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Antivenomics As a Tool to Improve the Neutralizing Capacity of the Crotalic Teixeira-Araújo et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2017) 23:28 DOI 10.1186/s40409-017-0118-7 SHORT REPORT Open Access Antivenomics as a tool to improve the neutralizing capacity of the crotalic antivenom: a study with crotamine Ricardo Teixeira-Araújo1,2, Patrícia Castanheira1, Leonora Brazil-Más2, Francisco Pontes1,2, Moema Leitão de Araújo3, Maria Lucia Machado Alves3, Russolina Benedeta Zingali1 and Carlos Correa-Netto1,2* Abstract Background: Snakebite treatment requires administration of an appropriate antivenom that should contain antibodies capable of neutralizing the venom. To achieve this goal, antivenom production must start from a suitable immunization protocol and proper venom mixtures. In Brazil, antivenom against South American rattlesnake (Crotalus durissus terrificus) bites is produced by public institutions based on the guidelines defined by the regulatory agency of the Brazilian Ministry of Health, ANVISA. However, each institution uses its own mixture of rattlesnake venom antigens. Previous works have shown that crotamine, a toxin found in Crolatus durissus venom, shows marked individual and populational variation. In addition, serum produced from crotamine-negative venoms fails to recognize this molecule. Methods: In this work, we used an antivenomics approach to assess the cross-reactivity of crotalic antivenom manufactured by IVB towards crotamine-negative venom and a mixture of crotamine-negative/crotamine-positive venoms. Results: We show that the venom mixture containing 20% crotamine and 57% crotoxin produced a strong immunogenic response in horses. Antivenom raised against this venom mixture reacted with most venom components including crotamine and crotoxin, in contrast to the antivenom raised against crotamine-negative venom. Conclusions: These results indicate that venomic databases and antivenomics analysis provide a useful approach for choosing the better venom mixture for antibody production and for the subsequent screening of antivenom cross-reactivity with relevant snake venom components. Keywords: Antivenom production, Antivenomics, Crotalus durissus, Crotamine, Crotoxin, Geographic venom variation Background led to the need for a more robust understanding of venom For over a century, antivenoms have remained the only composition and antivenom efficacy. effective treatment for snakebite. An important technical The preparation of representative mixtures of venoms consideration in the production of antivenoms is to use from snake species with a broad geographic distribution is suitable mixtures of venoms (as antigens) in order to not easy, particularly if there is no venomic-based produce neutralizing antibodies against the venom of the assessment to facilitate the selection of appropriate intended species. Although antivenom administration venom-producing specimens [1, 2]. In Brazil, six subspe- constitutes an effective therapy against envenomation, the cies of Crotalus durissus are currently recognized (C.d. occurrence of inter- and intraspecies venom variability has dryinas, C. d. marajoensis, C. d. ruruima, C. d. terrificus, C. d. cascavella, and C. d. collilineatus), with each inhabit- ing distinct ecosystems and displaying a wide geographical * Correspondence: [email protected] distribution [3–5]. All of these subspecies are capable of 1Laboratório de Hemostase e Venenos, Instituto de Bioquímica Médica producing lethal envenomation in humans, since their Leopoldo de Meis, Universidade Federal do Rio de Janeiro (UFRJ), Rio de venoms exhibit systemic neuro- and myotoxic activities. Janeiro, RJ, Brasil 2Departamento de Antígenos e Cultivo Celular, Instituto Vital Brazil, Niterói, Envenomation symptoms are often attributed to the RJ, Brasil presence of crotoxin and crotamine, although marked Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Teixeira-Araújo et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2017) 23:28 Page 2 of 8 differences in the concentration of these toxins among Material and methods venoms have been documented. For example, crotoxin, a Venoms and antivenoms neurotoxic phospholipase A2 (PLA2), is the main toxin The venoms of C. d. terrificus were obtained from cap- of C. durissus venom and accounts for 70–90% of its tive specimens maintained at the Regional Ophiology venom proteome [6–10]. On the other hand, significant Center of Porto Alegre (NOPA) and IVB. Crotamine- variation has been observed for crotamine at both indi- positive venom (batch 2014CDU00301) was extracted vidual and population levels, since it accounts from 2 up from 26 adult specimens (10 males and 16 females) to 22% of C. durissus proteome [9, 11–13]. There is also housed at NOPA. These snakes were collected primarily a positive correlation between the concentration of in Protásio Alves city, in the southern Brazilian state of crotamine present in venom and the level of crotamine Rio Grande do Sul. Crotamine-negative venom (batch gene expression (ranging from 1 to 32 copies per haploid 2014CDU00201) was extracted from 44 adult specimens genome) [12]. of both genders maintained by IVB. The latter snakes The Vital Brazil Institute (IVB) is one of three Brazilian were originally collected near Juiz de Fora in the state of institutions that manufacture antivenoms, the others be- Minas Gerais. Following venom extraction, samples were ing the Butantan Institute and Ezequiel Dias Foundation centrifuged at 1000 g to remove cell debris, lyophilized (FUNED). Although the crotalic antivenom produced by and stored at − 20 °C. the three institutions follows the guidelines defined by In accordance with the guidelines of the Brazilian Brazilian National Health Surveillance Agency (ANVISA), Pharmacopeia [21], and before preparing the mixture of each institution uses its own crotalic antigens. ANVISA venoms for immunization, the median lethal doses has determined that immunization should use crotamine- (LD50) for the crotamine-positive (batch 2014CDU00301) positive venom obtained from specimens that cover the and crotamine-negative (batch 2014CDU00201) venoms geographical distribution of C. durissus [5]. However, were determined as a quality control. The data available determination of the LD50 is the only quality control from internal registers of IVB indicated an LD50 of measure required for the venoms. 153 μg/kg, accessed via intraperitoneal (i.p.) route, for the The use of antivenomics to evaluate antivenom crotamine-positive venom (batch 2014CDU00301) and an efficacy was first described in an investigation of the LD50 of 73 μg/kg, i.p., for the crotamine-negative venom immunoreactivity of the polyvalent antivenom produced (batch 2014CDU00201). The mixture of venoms for by the Costa Rican Clodomiro Picado Institute (ICP) immunization was obtained by combining equal amounts against Bothriechis lateralis and Bothriechis schlegelii of crotamine-positive and negative venoms. venoms [14]. Subsequently, antivenomics has emerged The crotalic antivenom used in this study was pro- as a logical extension of venomic studies and has been duced at IVB (batches SAC085204b and SAC155204F), applied to numerous medically relevant species [1, 15, 16]. based on the guidelines of Brazilian Pharmacopeia, and In addition, antivenomics protocols have been extensively the instructions of ANVISA [5, 21]. This antivenom was revised and improved, and used in pre-clinical studies to of equine origin and consisted of purified F(ab’)2 frag- assess the efficacy of antivenoms and their potential ments. Antivenom SAC085204b, which expired in 2011, clinical applicability across the geographical range of a was from the same batch used in our previous antive- species [1, 2, 17–20]. nomics study [9]. The expiry date of the antivenom In a previous study, we applied a first generation batch SAC155204F is October, 2018. antivenomics approach to examine the immunoreactivity of crotalic antivenom against subspecies of Brazilian RP-HPLC venom fractionation rattlesnakes. The results indicated that the crotalic anti- Venom composition was assessed by reversed-phase venom was devoid of antibodies capable of recognizing high-performance liquid chromatography (RP-HPLC) and binding to crotamine [9]. This finding suggested ei- using a Shimadzu Prominence HPLC system. Pooled ther that the venom used in the production of the crota- crotamine-positive (batch 2014CDU00301) and pooled lic antivenom was devoid of crotamine, or that the low crotamine-negative (batch 2014CDU00201) venom sam- molecular mass of crotamine (4.8 kDa) meant that this ples were resuspended in 200 μL of 0.1% TFA and ap- cationic polypeptide could be a poor immunogen in plied to a Teknokroma Europa C18 column equilibrated horses. In order to explore further this question, the with solvent A (0.1% trifluoroacetic acid – TFA). Bound current study applied a second generation of antive- proteins were eluted
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