The role of complement in experimental cerebral malaria

Cerebral malaria (CM) is one of the most severe clinical complications of P. falciparum malaria with a fatality rate of 15-30%, and 10% of CM survivors have permanent neurological sequelae. Since inflammation is a central pathophysiological tenet of CM, we began examining the role of the complement system in pathogenesis of experimental cerebral malaria (ECM) using Plasmodium berghei ANKA (PbA) model. Previous studies using this model indicated that mice naturally deficient in complement component C5 were protected from cerebral complications, and wild type mice treated with anti-C5aR antibody were also protected. To determine the protective mechanism of naturally-C5 deficient mice, we examined C57BL/6 mice deficient in C5 as well as mice deficient in the anaphylatoxin receptors, C3aR and C5aR. While the C5 deficiency conferred protection, we found no significant difference in survival or clinical disease between wild type mice and the anaphylatoxin deficient mice, suggesting that protection from ECM in C5^-/- mice is not mediated through C5a-induced inflammation as previously reported. To determine if protection was mediated through prevention of C5b pairing with complement proteins C6-C9 to form the MAC, we treated wild type mice with an anti- C9 antibody specific for mouse C9 and found a significant increase in survival of treated mice. Interestingly, animals deficient in C3, a pathway component upstream of C5 were not significantly protected in ECM. Further investigation revealed C3^-/- animals had levels of C5a consistent with wild type animals, and treatment with anti-C9 antibody conferred protection. These results suggest that C5 is being cleaved in the absence of C3, and therefore the C5 convertase, and further supports that the pathological effects of complement in ECM are mediated at the level of C5 through the terminal complement pathway. These studies will hopefully provide new avenues of research for human studies; possibly using an anti-human C5 antibody, which is currently FDA approved to treat paroxysmal nocturnal hemoglobinuria.