6 research outputs found
Envenomations by Bothrops and Crotalus Snakes Induce the Release of Mitochondrial Alarmins
Skeletal muscle necrosis is a common manifestation of viperid snakebite envenomations. Venoms from snakes of the genus Bothrops, such as that of B. asper, induce muscle tissue damage at the site of venom injection, provoking severe local pathology which often results in permanent sequelae. In contrast, the venom of the South American rattlesnake Crotalus durissus terrificus, induces a clinical picture of systemic myotoxicity, i.e., rhabdomyolysis, together with neurotoxicity. It is known that molecules released from damaged muscle might act as ‘danger’ signals. These are known as ‘alarmins’, and contribute to the inflammatory reaction by activating the innate immune system. Here we show that the venoms of B. asper and C. d. terrificus release the mitochondrial markers mtDNA (from the matrix) and cytochrome c (Cyt c) from the intermembrane space, from ex vivo mouse tibialis anterior muscles. Cyt c was released to a similar extent by the two venoms whereas B. asper venom induced the release of higher amounts of mtDNA, thus reflecting hitherto some differences in their pathological action on muscle mitochondria. At variance, injection of these venoms in mice resulted in a different time-course of mtDNA release, with B. asper venom inducing an early onset increment in plasma levels and C. d. terrificus venom provoking a delayed release. We suggest that the release of mitochondrial ‘alarmins’ might contribute to the local and systemic inflammatory events characteristic of snakebite envenomations
Cross-recognition of a pit viper (Crotalinae) polyspecific antivenom explored through high-density peptide microarray epitope mapping
Snakebite antivenom is a 120 years old invention based on polyclonal mixtures of antibodies
purified from the blood of hyper-immunized animals. Knowledge on antibody recognition
sites (epitopes) on snake venom proteins is limited, but may be used to provide molecular
level explanations for antivenom cross-reactivity. In turn, this may help guide antivenom
development by elucidating immunological biases in existing antivenoms. In this study, we
have identified and characterized linear elements of B-cell epitopes from 870 pit viper venom
protein sequences by employing a high-throughput methodology based on custom designed
high-density peptide microarrays. By combining data on antibody-peptide interactions with
multiple sequence alignments of homologous toxin sequences and protein modelling, we
have determined linear elements of antibody binding sites for snake venom metalloproteases
(SVMPs), phospholipases A2s (PLA2s), and snake venom serine proteases (SVSPs). The
studied antivenom antibodies were found to recognize linear elements in each of the three
enzymatic toxin families. In contrast to a similar study of elapid (non-enzymatic) neurotoxins,
these enzymatic toxins were generally not recognized at the catalytic active site responsible
for toxicity, but instead at other sites, of which some are known for allosteric inhibition or for
interaction with the tissue target. Antibody recognition was found to be preserved for several
minor variations in the protein sequences, although the antibody-toxin interactions could
often be eliminated completely by substitution of a single residue. This finding is likely to have
large implications for the cross-reactivity of the antivenom and indicate that multiple different
antibodies are likely to be needed for targeting an entire group of toxins in these recognized
sites.Novo Nordisk Foundation/[NNF13OC0005613]/NNF/DinamarcaNovo Nordisk Foundation/[NNF16OC0019248]/NNF/DinamarcaUCR::VicerrectorÃa de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP
Não adesão ao tratamento medicamentoso contÃnuo: prevalência e determinantes em adultos de 40 anos e mais
Evaluation of antivenoms in the neutralization of hyperalgesia and edema induced by Bothrops jararaca and Bothrops asper snake venoms
Neutralization of hyperalgesia induced by Bothrops jararaca and B. asper venoms was studied in rats using bothropic antivenom produced at Instituto Butantan (AVIB, 1 ml neutralizes 5 mg B. jararaca venom) and polyvalent antivenom produced at Instituto Clodomiro Picado (AVCP, 1 ml neutralizes 2.5 mg B. aspar venom). The intraplantar injection of B. jararaca and B. asper venoms caused hyperalgesia, which peaked 1 and 2 h after injection, respectively. Both venoms also induced edema with a similar time course. When neutralization assays involving the independent injection of venom and antivenom were performed, the hyperalgesia induced by B. jararaca venom was neutralized only when bothropic antivenom was administered iv 15 min before venom injection, whereas edema was neutralized when antivenom was injected 15 min or immediately before venom injection. On the other hand, polyvalent antivenom did not interfere with hyperalgesia or edema induced by B. asper venom, even when administered prior to envenomation. The lack of neutralization of hyperalgesia and edema induced by B. asper venom is not attributable to the absence of neutralizing antibodies in the antivenom, since neutralization was achieved in assays involving preincubation of venom and antivenom. Cross-neutralization of AVCP or AVIB against B. jararaca and B. asper venoms, respectively, was also evaluated. Only bothropic antivenom partially neutralized hyperalgesia induced by B. asper venom in preincubation experiments. The present data suggest that hyperalgesia and edema induced by Bothrops venoms are poorly neutralized by commercial antivenoms even when antibodies are administered immediately after envenomation.Universidad de Costa Rica/[741-A1-027]/UCR/Costa RicaFundação de Amparo à Pesquisa do Estado de São Paulo/[98/00257-0]/FAPESP/BrasilFundação Butantan///BrasilUCR::VicerrectorÃa de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP