Biological properties of the d...
Biological properties of the digestive vacuole of Plasmodium falciparum: Activation of complement and coagulation
Plasmodium falciparum is an intracellular protozoan parasite that has been associated with humans since the dawn of time and causes severe forms of malaria. It is a major health problem around the globe and causes highest toll of death among children less than five years of age in developing countri...
Dasari, Prasad
Bhakdi, Sucharit (Prof. Dr.) (Thesis advisor)
Blutgerinnung
Plasmodium falciparum is an intracellular protozoan parasite that has been associated with humans since the dawn of time and causes severe forms of malaria. It is a major health problem around the globe and causes highest toll of death among children less than five years of age in developing countries. An infected female Anopheles mosquito injects malaria sporozoites into the skin while taking a blood meal. The sporozoites, which are released into the blood stream, reaches the liver where they undergo exoerythrocytic schizogony. After exoerythrocytic schizogony, millions of merozoites are released into the blood stream and infect new red blood cells, where they undergo erythrocytic schizogony in a cyclic manner. The erythrocytic schizogony stage of Plasmodium life cycle is where all clinical manifestations of malaria as a disease become apparent. The clinical symptoms like fever, headache, jaundice, vomiting have been associated with hyperparasitemia and these clinical symptoms coincide with the cyclical release of malaria parasites during schizonts rupture. A severe form of malaria develops as a consequence of capillaric sequestration of parasitized red blood cells (pRBC) and rosetting of pRBC with uninfected red blood cells which obstruct the blood flow to the brain. Activation of complement and coagulation, and increase in vascular permeability further aggravates severity of the disease which can lead to microcirculatory disturbances with comatous death as the ultimate outcome. Rupture of each Plasmodium falciparum infected red blood cell releases 8-32 infective merozoites along with a single digestive vacuole into the blood stream. The released digestive vacuole is an organelle in which hemozoin is surrounded by an intact membrane. We have discovered that the digestive vacuoles have the capacity to dually activate the complement and coagulation systems. Activation of complement and coagulation requires an intact DV membrane. The complement and coagulation activating properties of the DV are inhibited by low molecular weight dextran sulfate. In non-immune serum, DVs are opsonised with complement C3b and rapidly phagocytosed by polymorphonuclear granulocytes (PMN). Upon rupture, DVs lost its functional activities and the extracted malaria pigment from the DV organelle is not engulfed by the PMN. Liberated merozoites are not opsonized in non-immune serum and escape phagocytosis. High titered anti-malarial antibodies from immune patients mediate some uptake of the merozoites, but to an extent that is not sufficient to markedly reduce re-invasion rates. Engulfment of DVs by PMN induces a respiratory burst, but the generated reactive oxygen species (ROS) are unable to suppress the infective capacity of invading merozoites. Finally, ingested DVs drive the PMN into a state of functional exhaustion. Upon challenging of PMN with bacteria after DV ingestion, the ability to phagocytose bacteria prevails, but their capacity to mount a respiratory burst is reduced and microbicidal activity is compromised. We propose that these events might be linked to the development of septicemic episodes in patients with severe malaria in sub-Saharan African countries.
10.17192/z2013.0374
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