title: Biological properties of the digestive vacuole of Plasmodium falciparum: Activation of complement and coagulation
title: Biologische Eigenschaften der DV von Plasmodium falciparum
Creators: name: Dasari, Prasad
Publisher: name: Philipps-Universität Marburg
Year: 2013
Subjects: Complement
Malaria
Biowissenschaften, Biologie
Malaria , Coagulation
Blutgerinnung , Immunsystem

description: 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.
description: Die lebensbedrohliche Form der
      Malaria wird durch Plasmodium falciparum verursacht und geht
      einher mit schwerwiegenden Störungen des Gerinnungs- und
      Komplementsystems- Bei der Ruptur eines infizierten
      Erythrozyten werden 8 bis 32 Merozoiten und eine
      Nahrungsvakuole in die Blutbahn freigesetzt. Die
      Nahrungsvakuole (digestive vacuole = DV) ist ein
      membranumhülltes Organell, in dem das Abbauprodukt des
      Hämoglobins, das sog. Hämozoin, verpackt ist. Die
      Dissertationsarbeit befasst sich mit bislang unbekannten
      biologischen Eigenschaften der DV. Wir haben entdeckt, dass
      das freigesetzte Organell die bemerkenswerte Fähigkeit
      besitzt, den intrinsischen Gerinnungsweg und das
      Komplementsystem simultan zu aktivieren. Beide Vorgänge
      lassen sich mit niedermolekularem Dextransulfat inhibieren.
      Bindung von C3b bewirkt, dass DVs von neutrophilen
      Granulozyten selektiv phagozytiert werden. Die Phagozyten
      werden dabei aktiviert und es kommt zur Bildung von reaktiven
      Sauerstoffradikalen. Dieses treibt die Zellen in einen
      hypofunktionellen Zustand: während ihre Phagozytosefunktion
      erhalten bleibt, können aufgenommene Bakterien nicht mehr
      effizient abgetötet werden. Die DV stellt möglicherweise
      einen neuen Pathogenitätsfaktor des Malariaparasiten dar und
      könnte unmittelbar für tiefgreifende Störungen des
      Gerinnungssystems und des natürlichen Immunsystems
      verantwortlich sein.