Investigating degradation of basement membranes by Bothrops snake venoms to determine strategies for medical intervention

Abstract

Snakebite accidents is classified by the World Health Organization as a neglected tropical disease responsible for approximately 2.5 million cases of envenomation and 150,000 deaths per year, especially in rural regions of Africa, Asia, Latin America and Oceania. In Brazil, the Viperidae family represents the most important group of snakes for public health, as they are responsible for the majority of registered snakebite accidents. Among the effects resulting from these accidents, it is believed that hemostatic disturbances caused by the venoms of a wide variety of snake species play a central role in the pathophysiology of the envenomation and in the capture of prey. Snake venoms, especially those belonging to the Elapidae and Viperidae families, have several toxins that interact with the blood coagulation cascade and the fibrinolytic system. SVMPs can be the major components in Bothrops snake venoms and are classified into P-I, P-II or P-III. SVMPs are grouped with ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin motifs) proteins. Basement membranes (BM) are cell-adherent extracellular matrices and form sheet-like structures that underlie epithelia and surround most tissues. BMs are composed by laminins, collagen IV, nidogens, and the heparan sulfate proteoglycans (HSPGs) perlecan and agrin. SVMPs, just like ADAMs, can interact with BMs and degraded its components, leading to haemorrhage. In this context, venoms from Bothrops snakes can cause haemorrhage through the degradation of key structural components at the basement membrane, being classified as hemotoxic, since they present coagulotoxic (procoagulant) and haemorrhagic activities. Also, procoagulant venoms could cause venom-induced coagulopathy, which can exacerbate hemorrhage in envenomation.The intraspecific variability of snake venoms associated with their functional diversity is particularly critical when considering their reactivity with antivenom. For this reason, understanding the inter- and intraspecific variations in venomous snakes and their action on human envenoming is essential for the production and efficient use of antivenoms. In view of the complexity of the envenomation caused by snake species belonging to the Viperidae family and the relevance of these species to public health, the development of a multifaceted study comparing the coagulotoxic and haemorrhagic profile of the venoms of these species is extremely important. Thus, with the aim of complementing the characterisation of the coagulotoxic profile of individual venoms of species of snakes belonging to the genera Bothrops with high medical importance in different Brazilian regions (FAPESP PhD scholarship 2021/07627-5), this project proposes the characterisation of the degradation of basement membrane caused by the venom of the same snake species.