Envenomation, exposure to a toxin as a result of a bite or sting, can lead to local or systemic immunopathology and in some cases death. Snake bites are responsible for approximately 80000 deaths yearly, and highlights the need for development of novel therapeutics. It is particularly notable that the snakebite envenoming process presents some of the same clinical features observed in certain complement-mediated inflammatory conditions, making this system an interesting therapeutic target.
Researchers from Brazil, Australia and USA explored the complement system contribution to envenomation immunopathology by the snake Naja annulifera (snouted cobra), which occurs in several countries from Sub-Saharan Africa and causes accidents in human and dogs.
They observed that N. annulifera venom triggers complement activation mainly mediated by extrinsic routes dependent of the snake venom metalloproteinases action, culminating in anaphylatoxins generation and soluble Terminal Complement Complex assembly. They observed that that C5a anaphylatoxin biding to C5aR1 is responsible for several immunopathological reactions of the envenenomation, which triggers lipid mediators, chemokines and interleukins release in an in vitro human whole blood model.
In an experimental mouse model of envenomation, they demonstrated that C5a anaphylatoxin coupling to C5aR1 caused LTB4, PGE2, TXA2 release in subcutaneous tissue promoting endothelial dysfunctions which caused an extensive oedema. In addition C5a-C5aR1 signalling triggered CXCL1 release and neutrophils infiltration and activation, since high Myeloperoxidase (MPO) levels were detected. C5a-C5aR1 axis activation caused elevation on neutrophils and CCL2 and IL6 systemic levels in mouse exposed to moderate envenomation protocols.
Animals exposed to lethal envenomation protocols presented an intense Acute Lung Injury (ALI) and leukocytosis featured by neutrophilia and monocytosis, which were mediated by the C5-C5aR1 axis, since the treatment these animal with PMX205, a C5aR1 peptidic antagonist, abrogated all these effects.
Researchers concluded that they demonstrated for the first time, that activation of the C5a-C5aR1 axis is the main driver of the local and systemic reactions in envenomation by N. annulifera, a medically important snake on Sub-Saharan Africa.