Journal
FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.652242
Keywords
Naja snake venom; envenomation; complement system; C5a-C5aR1; complement inhibitors
Categories
Funding
- Sao Paulo Research Foundation (FAPESP) [2013/07467-1]
- CNPq Research Productivity Fellowship [301358/2017-6]
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The study revealed that Naja annulifera venom can activate the complement system, leading to the release of lipid mediators and chemokines, and subsequent pathological reactions. Inhibition of the C5a-C5aR1 axis can mitigate the effects of complement activation. The cyclic peptide antagonist PMX205 can rescue mice from systemic reactions and prevent acute lung injury caused by complement activation.
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.
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