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Parasitology Section Survival strategies of Plasmodium parasites in hepatocytes Zusammenfassung Wir benutzen den Nagerparasiten Plasmodium berghei als einen Modellorganismus, um die Überlebensstrategien von Plasmodien in Hepatozyten zu untersuchen. Im Hepatozyten leben die Plasmodien zunächst in einer parasitophoren Vakuole. Während der Merozoitenbildung wird die Vakuolenmembran zerstört und die Parasiten gelangen ins Wirtszellzytoplasma. In vitro konnten wir beobachten, dass sich die infizierten Zellen nach der Auflösung der Vakuolenmembran abrundeten und frei im Medium schwammen. Diese frei schwimmenden Zellen zeigten intrazellulär Eigenschaften von apoptotischen Zellen. Die Zellmembran blieb dagegen zunächst intakt, was den Schluss nahe legt, dass infizierte Zellen nicht von phagozytierenden Zellen erkannt und eliminiert werden können. Untersuchungen der molekularen Mechanismen dieser Parasit-Wirtszell Interaktionen sollen helfen, die Biologie des Leberstadiums von Plasmodien besser zu verstehen und Strategien zu entwickeln, die die Entwicklung der Parasiten in der Leber hemmen. Summary Using the rodent parasite Plasmodium berghei as a model system we investigate survival strategies of Plasmodium parasites in hepatocytes. Within the host cell Plasmodium parasites live initially in a parasitophorous vacuole. During merozoite formation the vacuole membrane is destructed and the parasites lie free in the host cell cytoplasm. In vitro we observed that upon the degeneration of the PVM, parasitised host cells rounded off and floated in the culture medium. These floating cells exhibited intracellular features of apoptotic cells. However, at first the cell membrane of the host cell remained intact suggesting that infected cells cannot be recognized and eliminated by phagocytising cells. Investigating the molecular mechanisms of these parasite-host cell interactions will help to understand the biology of the liver stage of Plasmodium and to improve strategies to inhibit the development of the parasite in the liver. Project Description and Results Malaria is caused by parasites of the genus Plasmodium and is transmitted by Anopheles mosquitoes. During a blood meal infected mosquitoes inject Plasmodium sporozoites into the skin of the mammalian host. From there the sporozoites reach the circulatory system and are transported to the liver, where they infect hepatocytes. The invasion of hepatocytes by Plasmodium 42 sporozoites is a well-documented event, but little is known how the parasite survives in the host cell and how exoerythrocytic merozoites are finally liberated. Although the host cell has principally the capacity to counteract the infection by committing suicide, Plasmodium parasites can obviously grow and develop intracellularly suggesting that the parasite interferes with pathways leading to programmed cell death (apoptosis). In order to investigate whether parasite infection protects the host cell from apoptosis, we treated two days infected cultures with concentrations of peroxide which induces programmed cell death in non-infected cells. Immunofluorescence studies revealed that infected cells are indeed protected against peroxide treatment confirming our assumption that the presence of the parasite confers resistance to apoptosis to its host cell. As long as the parasite develops and grows in the hepatocyte it is an advantage for the pathogen to support the survival of the host cell. But what happens when merozoites are formed which must leave the cell to infect red blood cells? We examined the final stage of parasite development in transformed hepatic cell lines and in primary hepatocytes in vitro and observed very interesting changes in infected cells. Three days post infection most P. berghei-infected cells lost adherence to the surface and to other cells in the culture. They rounded off and floated into the culture supernatant. Floating infected cells exhibited features of early apoptotic cells including nuclear condensation of the host cell nucleus, cytochrome c release from the mitochondria and caspase activation. However, another early marker of apoptosis, the loss of cell membrane asymmetry, could not be detected for several hours in infected floating cells and was only apparent briefly before merozoites are released. What could be the biological relevance of these observations? Our working hypothesis is that in vivo parasitised cells loose contact to their neighbouring cells and are bulged out between the normal hepatocytes. The later phases of intracellular parasite development are taking place in the space of disse or in the sinusoids of the liver (figure 1). Since the membrane of infected floating cells was found intact it is reasonable to assume that parasitised cells cannot be recognized by phagocytosing cells of the immune system. We believe that the observed membrane integrity in an otherwise apoptotic cell is actively preserved by the parasite and can thus be considered as a so far unknown immune evasion mechanism.
Figure 1: Suggested in vivo development of exoerythrocytic merozoites. KC: Kupffer cells, iHep: infected hepatocyte, RBC: red blood cells, EC: endothelial cells 43 Selected Publications • Saeftel M, Krueger A, Arriens S, Heussler V, Racz P, Fleischer B, Brombacher F, Hoerauf A. (2004). Mice deficient in interleukin-4 (IL-4) or IL-4 receptor alpha have higher resistance to sporozoite infection with Plasmodium berghei (ANKA) than do naive wild-type mice. Infect Immun 72: 322-31. • Heussler V.T., Rottenberg S., Schwab R., Kuenzi P., Fernandez P.C., McKellar S., Shiels B., Chen Z.J., Orth K., Wallach D., Dobbelaere D.A. (2002). Hijacking of host cell IKK signalosomes by the transforming parasite Theileria, Science 298: 1033-6. • Heussler V., Küenzi P., Fraga F., Hemmings B., Dobbelaere D. (2001). Differential role for the PI 3-kinase-Akt pathway in proliferation and survival of Theileria-transformed Leukocytes. Cell Microbiol 3: 1-15 • Heussler V., Fernandez P., Machado J., Botteron C., Dobbelaere D. (1999). The intracellular parasite Theileria parva protects infected T cells from apoptosis, Proc Natl Acad Sci USA 96: 7312-7 Cooperating Partners • Andreas Krüger, Department of Molecular Parasitology, BNI • Mo Klinkert, Department of Molecular Medicine, BNI • Stefan Huber, University of Tübingen • Maria Mota, Instituto Gulbenkian de Cienia, Oeiras, Portugal Investigators • Volker Heussler • Stefanie Bolte • Ulrike Fröhlke • Sebastian Horstmann • Gunnar Müller • Claudia van de Sand Parasitology Section
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