Investigating the molecular mechanism of Glycosylphosphatidylinositol-dependent signalling and its implication in the development of severe malaria pathology
Final Report Abstract
The main goal of this work was to investigate additional aspects of the interaction of plasmodial GPI with the host. This was achieved specifically first through investigation of the transfer of plasmodial antigens, including GPI to the host cell surface and its implication and second through investigation of the mechanism of GPI-dependent signaling. The transfer of plasmodial antigens to the surface of non parasitized host cells was investigated using biochemical and cell biological approaches that enabled the specific isolation and characterization of plasmodium-derived microvesicles as the ultimate vehicle that mediates that transfer. We could establish that the transfer of parasitic material to the surface of non parasitized red blood cells prime them for destruction by the host immune system. In this respect macrophages were shown to specifically target and destroy non-infected red blood cells that had been decorated with parasitic antigens by co-incubation with parasite-derived microvesicles. This process we believe, when occurring in vivo, might contribute to the development of malaria dependent anemia and explain the observed discrepancy between parasitemia and anemia. The role of Plasmodium glycosylphosphatidylinositol (GPI)-moesin interaction in the development of malaria pathology was investigated by determining the pro-inflammatory response of moesin-deficient macrophages and dendritic cells in vitro as well as the extent of experimental cerebral malaria (ECM)-associated mortality and systemic immune response of moesin-deficient mice in vivo. The induction of immune responses and the development of ECM were found to be moesin-independent in these settings. In addition, the host chemokine response during ECM, P. berghei ANKA as a model of ECM and the non-lethal strain P. berghei NK65 were used to determine the potential contribution of chemokines in the pathogenesis of ECM. Systemic immune responses were demonstrated to be independent of the parasite strain and parasitemia, while pro-inflammatory immune responses were much more pronounced in brains of mice which succumbed to ECM. Additionally, in vitro endothelial cell stimulation with P. berghei ANKA and P. berghei NK65 revealed that the extent of endothelial cell chemokine secretion is strain-dependent. Together, these data indicate that local chemokine responses might be critical in determining disease outcome. Collectively, this work contributes to advancing the understanding severe malaria pathogenesis, which is pivotal for the development of advanced parasite-eliminating and immunomodulatory strategies to combat malaria and its associated pathology.
Publications
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Human C1-Inhibitor suppresses malaria parasite invasion and cytoadhesion via binding to parasite glycosylphosphatidylinositol and host cell receptors. J Infect Dis. 2015 Sep 7
Mejia P, Diez-Silva M, Kamena F, Lu F, Fernandes SM, Seeberger PH, Davis AE 3rd, Mitchell JR
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Cytokines and Chemokines in Cerebral Malaria pathogenesis. Front. Cell Infect Microbiol., Jul 2017
Dunst J, Kamena F and Matuschewski K
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Interaction between Plasmodium Glycosylphosphatidylinositol and the host protein moesin has no implication in Malaria pathology. Front. Cell. Infect. Microbiol., May 2017
Dunst J, Azzouzz N, Liu X, Tsukita S, Seeberger PH and Kamena F
