Absence of complement terminal pathway activity in C6-deficient mice prolongs survival in a mouse model of severe...

Malaria is an important and serious parasite-induced disease associated with severe anemia and multiple organ failure (MOF) that can be lethal in humans. We explored the contribution of the terminal pathway of complement in a mouse model of malaria-induced lethal MOF following infection with Plasmodium (P.) bergei.

We compared organ damage and survival between C57BL/6 J mice deficient in the terminal pathway component C6 (C6def) and wild type C57BL/6 J mice (WT) after intraperitoneal injection of 10⁶P. bergei-parasitized erythrocytes. We measured survival, relevant blood parameters, assessed severity of injury and complement activation in relevant organs.

All WT mice died between 7 and 13 days after exposure to the parasite challenge; in contrast, C6def mice showed prolonged survival with 80 % alive at day 20, although all then died by day 26. Parasite load and anemia at day 7 were similar in C6def and WT mice. Liver and lung injuries, fibrosis and organ complement deposition assessed at day 7 post-infection were significantly milder in C6def mice compared to WT. Blood platelet count at day 7 post-infection was markedly reduced in WT but not in C6def mice; in contrast, white cell count was increased and hemoglobin levels decreased to similar degrees in WT and C6def mice post-infection. Albumin levels were reduced, significantly more in WT, while blood markers of liver injury were increased, significantly more in WT. Serum levels of complement activation product, C5a, and IL6 were increased in both groups, the latter significantly higher in WT versus C6def mice.

We show that complement terminal pathway activation exacerbates organ injuries and thrombocytopenia associated with P. bergei infection, contributing to rapid progression to death in the model. Inhibition of terminal pathway activation in human malarial infections using available drugs might slow progression to organ failure, extending the window of opportunity for the effective use of anti-malarial medicines.