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• W2924046872 abstract "Malaria remains one of the leading public health challenges mankind is facing today. An infection in the mammalian host is initiated when Plasmodium sporozoites are inoculated into the skin through the bite of an infected female Anopheles mosquito. The parasites then enter a blood vessel and travel with the bloodstream to the liver, their initial site of replication. The exact route that malaria sporozoites take to invade hepatocytes has been subject of extensive discussion. Previous studies suggest that sporozoites cross the sinusoidal cell barrier by passing through Kupffer cells, the resident macrophages of the liver, but interpretation of these results was hampered by various factors and proof has been elusive. One aim of this thesis was to determine the role of Kupffer cells as potential entrance gates for Plasmodium yoelii sporozoites to the liver. Two different mouse models were used to achieve this goal: 1) Op/op mice, which have 77% fewer Kupffer cells in relation to their phenotypically normal +/? littermates, and 2) mice treated with liposome-encapsulated clodronate, which completely eliminates Kupffer cells from the liver. A novel quantitative reverse transcription polymerase chain reaction assay for P. yoelii 18S rRNA revealed an 84% reduced liver infection rate in op/op mice compared to control littermates. In contrast, infection with P. yoelii was enhanced seven- to 15-fold in clodronate-treated mice. The discrepancy between these two mouse models was explained by electron microscopy showing temporary discontinuities in the sinusoidal cell layer caused by clodronate treatment. Thus, Kupffer cell deficiency in op/op mice reduces sporozoite infection by diminishing the number of portals to the liver parenchyma, whereas clodronate increases sporozoite infection by opening portals and providing sporozoites direct access to hepatocytes. Together these data provide strong support that Kupffer cell passage is obligatory for Plasmodium infection of the liver. After successful hepatocyte invasion, sporozoites develop to large exo-erythrocytic forms (EEF) which eventually differentiate to thousands of erythrocyte infective merozoites. These merozoites are released into the bloodstream and cause the typical symptoms of a malaria infection. EEFs are key vaccine and drug targets but until recently, morphological analysis of Plasmodium growth and development in the liver was restricted to post-mortem investigations and in vitro studies. The second focus of this thesis was to characterize the process of EEF maturation and the mechanism of merozoite release in vivo. Intravital microscopy of GFP-expressing P. yoelii parasites showed that merozoites are predominantly released from infected hepatocytes as merosomes, packets of dozens to hundreds of parasites enveloped by host cell membrane. Merosomes exit the liver intact, adapt a relatively uniform size and accumulate in the lungs. The pulmonary microvasculature effectively cleared merosomes from the bloodstream and no large parasite aggregates were found in blood harvested from the tail vein or the left heart or in any of the major organs. Characterization of isolated extrahepatic merosomes with apoptotic markers, membrane dyes and nucleic acid stains revealed that merosomes have an intact membrane and contain viable merozoites. Evidence of merosomal merozoite infectivity was provided by hepatic effluent containing merosomes being significantly more infective than blood with an identical low-level parasitemia. After being arrested inside lung capillaries, merosomes eventually disintegrated thus liberating merozoites into the bloodstream. This previously unrecognized phase of the Plasmodium life cycle is considered advantageous for the parasite, because the low intravascular macrophage density and the reduced blood velocity in the lung very likely enhance the ability of merozoites to successfully invade erythrocytes. Together, these findings suggest that Plasmodium has acquired yet another mechanism to evade the hosts’ immune system: merosomes protect merozoites from phagocytosis and safely shuttle them out of the liver, thus ensuring an effective transition from the silent liver to the clinically symptomatic blood phase of the malaria infection." @default.
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• W2924046872 date "2007-01-01" @default.
• W2924046872 modified "2023-09-27" @default.
• W2924046872 title "The liver phase of malaria infection" @default.
• W2924046872 hasPublicationYear "2007" @default.
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