Abstract
Systemic complement activation drives a plethora of pathological conditions, but its role in snake envenoming remains obscure. Here, we explored complement’s contribution to the physiopathogenesis of Naja annulifera envenomation. We found that N. annulifera venom promoted the generation of C3a, C4a, C5a, and the soluble Terminal Complement Complex (sTCC) mediated by the action of snake venom metalloproteinases. N. annulifera venom also induced the release of lipid mediators and chemokines in a human whole-blood model. This release was complement-mediated, since C3/C3b and C5a Receptor 1 (C5aR1) inhibition mitigated the effects. In an experimental BALB/c mouse model of envenomation, N. annulifera venom promoted lipid mediator and chemokine production, neutrophil influx, and swelling at the injection site in a C5a-C5aR1 axis-dependent manner. N. annulifera venom induced systemic complementopathy and increased interleukin and chemokine production, leukocytosis, and acute lung injury (ALI). Inhibition of C5aR1 with the cyclic peptide antagonist PMX205 rescued mice from these systemic reactions and abrogated ALI development. These data reveal hitherto unrecognized roles for complement in envenomation physiopathogenesis, making complement an interesting therapeutic target in envenomation by N. annulifera and possibly by other snake venoms.
Highlights
Complement activation is a crucial event influencing the development of innate and adaptive immune responses [1, 2]
To determine whether N. annulifera venom could interfere with the complement activity, normal human serum (NHS) samples were incubated with the venom and submitted to hemolytic (AP and CP) and C4b (LP) Enzyme-Linked Immunosorbent Assay (ELISA) assays [41, 42]
We found that N. annulifera venom triggered anaphylatoxin generation and soluble Terminal Complement Complex (sTCC) assembly (Supplementary Figure 1); these processes were accompanied by the release of lipid mediators, including leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and thromboxane A2 (TXA2) (Supplementary Figure 2)
Summary
Complement activation is a crucial event influencing the development of innate and adaptive immune responses [1, 2]. Once microbial associated molecular patterns (MAMPs) and damageassociated molecular patterns (DAMPs) have been detected, complement can become activated through three intrinsic pathways, the alternative (AP), lectin (LP), and classical (CP) pathways, or through extrinsic pathways involving coagulation proteases, cathepsins, elastase, or snake venom metalloproteases and serine proteases [2, 3]. All of these pathways converge at central events that culminate in the cleavage of C3, C4, and/or C5, leading to the generation of opsonins (C3b and C4b) and anaphylatoxins (C3a, C4a, and C5a) and assembly of the terminal complement complex Such results have been observed in a myriad of inflammatory disorders [16,17,18,19], as well as in envenomation by snakes [20]
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