title: Pathogenesis of malaria revisited.
abstract: Plasmodium falciparum malaria claims 1 million lives around the globe every year. Parasitemia can reach remarkably high levels. The developing parasite digests hemoglobin and converts the waste product to hemozoin alias malaria pigment. These processes occur in a vesicular compartment named the digestive vacuole (DV). Each parasitized cell releases one DV upon rupture. Myriads of DVs thus gain entry into the blood, but whether they trigger pathobiological events has never been investigated. We recently discovered that the DV membrane simultaneously activates the two major enzyme cascades in blood, complement and coagulation. Activation of both is known to occur in patients with severe malaria, so discovery of the common trigger has large consequences. The DV membrane but not the merozoite has the capacity to spontaneously activate the alternative complement and intrinsic clotting pathway. Ejection of merozoites and the DV into the bloodstream, therefore, results in selective opsonization and phagocytosis of the DV, leaving merozoites free to invade new cells. The DV membrane furthermore has the capacity to assemble prothrombinase, the key convertase of the intrinsic clotting pathway. The dual capacity of the DV to activate both complement and coagulation can be suppressed by low-molecular-weight dextran sulfate. This agent protects experimental animals from the detrimental consequences, resulting from intravenous application of purified DVs. Phagocytosis of DVs not only deploys PMN away from merozoites, but also drives the cells into a state of functional exhaustion. This may be one reason for the enhanced susceptibility of patients with severe malaria toward systemic bacterial infections. Together, these findings indicate that the DV may represent a hitherto unrecognized, important determinant of parasite pathogenicity.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg University Mainz, Hochhaus Augustusplatz, 55101 Mainz, Germany.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dasari
authors.forename: Sucharit
authors.initials: S
authors.lastname: Bhakdi
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D003167:Complement Activation; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology / Q000473:pathology*; D018512:Parasitemia / Q000503:physiopathology*; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D014617:Vacuoles / Q000378:metabolism*