New Insights into Immunopathology Associated to Bothrops lanceolatus Snake Envenomation: Focus on PLA2 Toxin

Abstract

The systemic increase in inflammatory mediator levels can induce diverse pathological disorders, including potentially thrombus formation, which may be lethal. Among the clinical conditions in which the formation of thrombi dictates the patient’s prognosis, envenomation by Bothrops lanceolatus should be emphasized, as it can evolve to stroke, myocardial infarction and pulmonary embolism. Despite their life-threatening potential, the immunopathological events and toxins involved in these reactions remain poorly explored. Therefore, in the present study, we examined the immunopathological events triggered by a PLA2 purified from B. lanceolatus venom, using an ex vivo human blood model of inflammation. Our results showed that the purified PLA2 from the venom of B. lanceolatus damages human erythrocytes in a dose dependent way. The cell injury was associated with a decrease in the levels of CD55 and CD59 complement regulators on the cell surface. Moreover, the generation of anaphylatoxins (C3a and C5a) and the soluble terminal complement complex (sTCC) indicates that human blood exposure to the toxin activates the complement system. Increased production of TNF-α, CXCL8, CCL2 and CCL5 followed complement activation. The venom PLA2 also triggered the generation of lipid mediators, as evidenced by the detected high levels of LTB4, PGE2 and TXB2. The scenario here observed of red blood cell damage, dysfunctions of the complement regulatory proteins, accompanied by an inflammatory mediator storm, suggests that B. lanceolatus venom PLA2 contributes to the thrombotic disorders present in the envenomed individuals.

Bothrops venom-induced hemostasis disorders in the rat: Between Scylla and Charybdis

“…This result confirms an ex vivo model based on human whole blood, in which this venom elicited an inflammatory reaction combining pro-inflammatory interleukin production (IL-1β, IL-6 and TNF-α), chemokine upregulation (MCP-1, RANTES and IL-8), complement activation and eicosanoid release (leukotriene B 4 , prostaglandin E 2 and thromboxane B 2 ) [76]. These events were triggered by PLA 2 isolated from B. lanceolatus venom [77]. In various other conditions including the coronavirus disease-2019, cytokine storm affects components of hemostasis, including endothelial cells, platelets, coagulation cascade, and fibrinolytic pathway, leading to hypercoagulability named thromboinflammation thus increasing the risk of thrombosis [78].…”

A murine experimental model of the unique pulmonary thrombotic effect induced by the venom of the snakeBothrops lanceolatus

“…However, inhibition of SVMPs did not prevent the formation of thrombi, although abrogated pulmonary hemorrhage, thus evidencing that thrombosis occurs in conditions where SVMPs are inhibited and implying that other as yet unidentified components are responsible for this effect. The proinflammatory effect of B. lanceolatus venom, reflected by its ability to activate the complement system and generate a variety of mediators, has been proposed as a possible mechanism of the thrombotic effect [16][17][18]. Alternative mechanisms of thrombosis might be related to the action of venom on von Willebrand factor, promoting its binding to type VI collagen in the subendothelial surface [15] or to platelet activation, perhaps associated with the thrombocytopenia observed in clinical cases in in our experimental conditions.…”

“…It has been proposed that venom-induced alterations in the endothelium might be involved [12,13,14]. Other proposed mechanisms include platelet activation, the effect of venom on the binding of von Willebrand factor to type VI collagen in the subendothelium [15], and the proinflammatory activity of the venom [16][17][18]. Proteomic analysis of adult specimens of B. lanceolatus venom have revealed a pattern characteristic of viperid snake venoms, with predominance of P-III and P-I metalloproteinases (SVMPs), serine proteinases (SVSPs), phospholipases A 2 (PLA 2 s) and, to a lower extent, L-amino acid oxidases and C-type lectin like proteins (SNACLECs), disintegrins, and cysteine-rich secretory proteins (CRISPs) [14,19].…”