Abstract
Envenomation by Bothrops snakes causes prominent local effects, including pain, oedema, local bleeding, blistering and necrosis, and systemic manifestations, such as hemorrhage, hypotension, shock and acute renal failure. These snake venoms are able to activate the complement system and induce the generation of anaphylatoxins, whose mechanisms include the direct cleavage of complement components by snake venom metalloproteinases and serine proteinases present in the venoms. A metalloproteinase able to activate the three complement pathways and generate active anaphylatoxins, named C-SVMP, was purified from the venom of Bothrops pirajai. Considering the inflammatory nature of Bothrops venoms and the complement-activation property of C-SVMP, in the present work, we investigated the inflammatory effects of C-SVMP in a human whole blood model. The role of the complement system in the inflammatory process and its modulation by the use of compstatin were also investigated. C-SVMP was able to activate the complement system in the whole blood model, generating C3a/C3a desArg, C5a/C5a desArg and SC5b-9. This protein was able to promote an increase in the expression of CD11b, CD14, C3aR, C5aR1, TLR2, and TLR4 markers in leukocytes. Inhibition of component C3 by compstatin significantly reduced the production of anaphylatoxins and the Terminal Complement Complex (TCC) in blood plasma treated with the toxin, as well as the expression of CD11b, C3aR, and C5aR on leukocytes. C-SVMP was able to induce increased production of the cytokines IL-1β and IL-6 and the chemokines CXCL8/IL-8, CCL2/MCP-1, and CXCL9/MIG in the human whole blood model. The addition of compstatin to the reactions caused a significant reduction in the production of IL-1β, CXCL8/IL-8, and CCL2/MCP-1 in cells treated with C-SVMP. We therefore conclude that C-SVMP is able to activate the complement system, which leads to an increase in the inflammatory process. The data obtained with the use of compstatin indicate that complement inhibition may significantly control the inflammatory process initiated by Bothrops snake venom toxins.
Highlights
Snakebite envenoming was recently included in the World Health Organization (WHO) list of neglected tropical diseases due to its high incidence and severity [1]
The local and systemic effects of Bothrops envenomation are closely related to the presence of certain classes of toxins in the venoms, such as snake venom metalloproteinases (SVMPs), serine proteinases, phospholipases A2 (PLA2s), C-type lectins, L-amino acid oxidases (LAO), and hyaluronidases [6, 7], among which there are toxins able to activate the complement system [4], contributing to the inflammatory symptoms observed in envenomed patients
Incubation of human blood with LPS or C-SVMP resulted in a significant increase in C3a/C3a desArg (Figure 1A), C5a/C5a desArg (Figure 1B) and SC5b9 (Figure 1C) plasma levels compared to those from samples incubated with PBS, indicating activation of the complement system
Summary
Snakebite envenoming was recently included in the World Health Organization (WHO) list of neglected tropical diseases due to its high incidence and severity [1]. Belonging to the Viperidae family, the Bothrops genus comprises more than 20 species in the Americas, the majority of which are classified as Category 1 by the WHO, which means they are “highly venomous snakes that are common or widespread and cause numerous snakebites, resulting in high levels of morbidity, disability or mortality” [5]. The local and systemic effects of Bothrops envenomation are closely related to the presence of certain classes of toxins in the venoms, such as snake venom metalloproteinases (SVMPs), serine proteinases, phospholipases A2 (PLA2s), C-type lectins, L-amino acid oxidases (LAO), and hyaluronidases [6, 7], among which there are toxins able to activate the complement system [4], contributing to the inflammatory symptoms observed in envenomed patients
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