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.

C3 deficiency in humans is a rare disorder characterized by severe recurrent infections. We identified the mutations responsible for a complete homozygous C3 deficiency. Sequencing of the proband C3 cDNA (5067 bp) revealed the following alterations: (a) a silent G-->A transition at nucleotide 972; (b) a T-->C substitution at nucleotide 1001 resulting in a L314P transition; and (c) a stop codon in exon 13 caused by a G-->A substitution at position 1716. The presence of the same premature termination codon was confirmed in approximately half the clones obtained from the proband's paternal and maternal genomic DNAs. Finally, the proband produced approximately 20-fold less C3 mRNA than the normal control. Therefore, in addition to the fact that no functional protein will be synthesized in the deficient cells, this nonsense mutation may be associated with the low C3 mRNA levels.

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Complement and dendritic cells (DCs) are essential components of innate immunity. Both participate in local inflammation and moreover have roles in the initiation of the acquired immunity response and in the maintenance of tolerance. Recent studies have demonstrated the ability of DCs to synthesize C1q, C3, Factor I, Factor B and complement receptors 3 and 4. In this study, we demonstrate that human DCs are a source of other soluble complement proteins including C1q, C4b binding protein (C4BP), C7 and C8. Complement receptors (CR)1 and the CD18 chain (common for CR3 and CR4) were also present on DCs while CR2 was not detected.