P-I snake venom metalloproteinase is able to activate the complement system by direct cleavage of central components of the cascade

Pidde-Queiroz, G, Magnoli, F, Portaro, F, Serrano, S, Lopes, A, Paes Leme, A, Van Den Berg, Carmen and Tambourgi, D 2013. P-I snake venom metalloproteinase is able to activate the complement system by direct cleavage of central components of the cascade. PLoS Neglected Tropical Diseases 7 (10) , e2519. 10.1371/journal.pntd.0002519

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Abstract

Background Snake Venom Metalloproteinases (SVMPs) are amongst the key enzymes that contribute to the high toxicity of snake venom. We have recently shown that snake venoms from the Bothrops genus activate the Complement system (C) by promoting direct cleavage of C-components and generating anaphylatoxins, thereby contributing to the pathology and spread of the venom. The aim of the present study was to isolate and characterize the C-activating protease from Bothrops pirajai venom. Results Using two gel-filtration chromatography steps, a metalloproteinase of 23 kDa that activates Complement was isolated from Bothrops pirajai venom. The mass spectrometric identification of this protein, named here as C-SVMP, revealed peptides that matched sequences from the P-I class of SVMPs. C-SVMP activated the alternative, classical and lectin C-pathways by cleaving the α-chain of C3, C4 and C5, thereby generating anaphylatoxins C3a, C4a and C5a. In vivo, C-SVMP induced consumption of murine complement components, most likely by activation of the pathways and/or by direct cleavage of C3, leading to a reduction of serum lytic activity. Conclusion We show here that a P-I metalloproteinase from Bothrops pirajai snake venom activated the Complement system by direct cleavage of the central C-components, i.e., C3, C4 and C5, thereby generating biologically active fragments, such as anaphylatoxins, and by cleaving the C1-Inhibitor, which may affect Complement activation control. These results suggest that direct complement activation by SVMPs may play a role in the progression of symptoms that follow envenomation. Author Summary The genus Bothrops inflicts the vast majority of snakebites in Central and South America and is responsible for 90% of snake envenomations in Brazil. Envenomations are characterized by prominent local effects, including edema and necrosis, and by systemic manifestations such as hemorrhage, coagulopathy and acute renal failure. Several components have been isolated from Bothrops venoms, and the snake venom metalloproteinases (SVMPs) are key enzymes contributing to the high toxicity of the venoms. Previously, we analyzed the pro-inflammatory properties of snake venoms from the genus Bothrops and demonstrated that several of them were potent activators of the Complement (C) system. C3a, C4a and C5a were generated in venom-treated sera not only through C-activation but also by direct cleavage of C-components. In the present study, we have isolated and characterized a metalloproteinase from Bothrops pirajai snake venom, named here as C-SVMP, which interferes with all three complement pathways, generating potent pro-inflammatory fragments, such as C3a, C4a and C5a. Our data suggest that C-activation by Bothrops pirajai venom is due to activity of an SVMP, which may play a role in the progression of symptoms that follow envenomation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Public Library of Science
ISSN:	1935-2727
Date of First Compliant Deposit:	9 April 2018
Date of Acceptance:	21 September 2013
Last Modified:	21 May 2023 09:35
URI:	https://orca.cardiff.ac.uk/id/eprint/110570

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