Malaria remains one of the most deadly infectious diseases throughout the developing world especially among children [1]. Despite decades of effort, attempts at immunological control of this parasite through vaccine development have not been successful. This failure is, in large part, due to our poor understanding of the host immune response to the parasite both at the level of innate and adaptive immunity [2]. 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. In CM the brain microvasculature is characterized by an activated endothelium, occlusion of vessels with parasite-infected RBCs (iRBCs), platelets and leukocytes [3-5]. In addition to microvasculature pathology, we have recently observed evidence of significant neurodegeneration manifested by structural and transcriptional changes in Purkinje cells and disruptions in myelination in the cerebellum during ECM. Numerous proinflammatory mediators have been shown to contribute to the development of CM [3, 4, 6] but a comprehensive understanding of how these immune components interact and lead to central nervous system (CNS) disease is lacking. Since inflammation is a central pathophysiological tenet of CM, we began examining the role of the complement system in the development and pathogenesis of experimental cerebral malaria (ECM) using the Plasmodium berghei ANKA (PbA) model system [3, 5, 6]. We have recently reported that C5-/- mice are significantly protected from ECM due to the loss of membrane attack formation [14], not to the loss of C5a-mediated effects as previously reported [29, 30], since C5a receptor-deficient (C5aR-/-) mice are fully susceptible to ECM. Our preliminary results now demonstrate that inhibition of the classical and alternative complement pathways (via C4-/- and factor B-/- mice, respectively) does not alter ECM susceptibility. Importantly we have also observed that clinical signs of ECM in C3-/- mice are significantly more severe than in C5-/- mice. Together these data indicate that the classical and alternative pathway C5 convertases (both of which contain C3b derived from C3 cleavage) are not required for C5 cleavage in ECM. Rather our data suggest that the more recently described complement """"""""extrinsic protease activation pathway"""""""" may be responsible for cleaving C5 to functionally active C5a and C5b in ECM [15, 17, 18]. These findings raise important questions regarding the role of complement in ECM. For example, how does C5 mechanistically contribute to ECM development and progression? What is the relative importance of extrinsic protease activation pathway (via proteases such as thrombin and plasmin) to C5- mediated inflammation in ECM? Based on our preliminary observations, we hypothesize that C5 is the critical complement inflammatory effector molecule in ECM and that activation of C5 via the extrinsic protease activation pathway leads to complement-mediated pathology in ECM.
Malaria remains one of the most deadly infectious diseases throughout the developing world especially among children [1]. Despite decades of effort, attempts at immunological control of this parasite through vaccine development have not been successful, and this failure is, in large part, due to our poor understanding of the host immune response to the parasite both at the level of innate and adaptive immunity [2]. 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.
