The Membrane Attack Complex of complement is required for the development of murine Experimental Cerebral Malaria (112.2)

Abstract

Abstract Cerebral malaria (CM) is a severe complication of P. falciparum malaria with a 15-30% fatality and 10% of CM survivors have permanent neurological sequelae. Since inflammation is key to CM development, we examined the role complement in experimental cerebral malaria (ECM) development using the P. berghei model. Previous studies indicated that C5-/- mice were protected in ECM. To determine the role of complement activation, we examined mice deficient in pathway specific components, C4 and Factor B, as well as C3, which forms the C5 convertase. We found no differences in survival between wild type (WT) and C4 or Factor B deficient mice. We observed moderate protection in C3-/- mice, suggesting that blocking C5 cleavage is important in ECM development. We found that complement anaphylatoxin receptor deficient mice were not protected, suggesting that the mechanism of protection in C5-/- mice is not mediated through C5a-induced inflammation. We next examined C5b indirectly by treating WT mice with anti-C9 antibody and found significant increase in survival. We also treated C3-/- mice with anti-C9 antibody to determine if blocking MAC in these mice could abrogate disease, and found significant protection in treated mice compared to controls. Our results suggest that pathological effects of complement in ECM are primarily mediated at C5 through the terminal pathway and that this is occurring even in the absence of C3 suggesting an alternative mechanism for C5 cleavage in C3-/- mice.