The relationship between clinics and the venom of the causative Amazon pit viper (Bothrops atrox)

Author summary Bothrops atrox is a snake of major medical importance in the Amazon. Its venom is specialized to kill preys in the nature, especially because of coagulotoxic and proteolytic activities. B. atrox envenomings cause local inflammation and, in a significant proportion, systemic manifestations, namely bleeding disorders. These signs and symptoms are caused by the various toxins present in the venom of this snake, which act in the organism by different mechanisms. It is not known to what extent the composition of the venom that was inoculated by the snake that caused the envenoming can influence the patient's clinical condition. To study this subject, this work correlated the constituents of the venom with the clinical manifestations of hospitalized patients, taking advantage of the fact that many patients bring the snake responsible for the bite. The abundance of each toxin family was similar among the venom samples, but the variants composition of each toxin was highly variable. Considering the protein families, a group named metalloproteases (SVMP) presented the best correlation with bleeding disorders and edema. Some variants of venom SVMPs, and other toxin families, such as C-type lectin-like toxins (CTL) and snake venom serine proteinases (SVSP) presented correlation to signs and symptoms presented by the patients as bleeding disorders, edema, ecchymosis and blister formation. Our results show that venom composition modulates clinical manifestations of snakebites. Snake venoms are complex mixtures of proteins with toxic activities, with many distinct isoforms, affecting different physiological targets, comprised in a few protein families. It is currently accepted that this diversity in venom composition is an adaptive advantage for venom efficacy on a wide range of prey. However, on the other side, variability on isoforms expression has implications in the clinics of human victims of snakebites and in the efficacy of antivenoms. B. atrox snakes are responsible for most of the human accidents in Brazilian Amazon and the type and abundance of protein families on their venoms present individual variability. Thus, in this study we attempted to correlate the individual venom proteome of the snake brought to the hospital by the patient seeking for medical assistance with the clinical signs observed in the same patient. Individual variability was confirmed in venoms of the 14 snakes selected for the study. The abundance of each protein family was quite similar among the venom samples, while the isoforms composition was highly variable. Considering the protein families, the SVMP group presented the best correlation with bleeding disorders and edema. Considering individual isoforms, some isoforms of venom metalloproteinase (SVMP), C-type lectin-like toxins (CTL) and snake venom serine proteinases (SVSP) presented expression levels that with statistically significant positive correlation to signs and symptoms presented by the patients as bleeding disorders, edema, ecchymosis and blister formation. However, some unexpected data were also observed as the correlation between a CTL, CRISP or LAAO isoforms with blister formation, still to be confirmed with a larger number of samples. Although this is still a small number of patient samples, we were able to indicate that venom composition modulates clinical manifestations of snakebites, to confirm at the bedside the prominent role of SVMPs and to include new possible toxin candidates for the development of toxin inhibitors or to improve antivenom selectiveness, important actions for the next generation treatments of snakebites.