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Gruring, Christof

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Gruring

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Christof

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Gruring, Christof
Author's Publications: search.filters.isAuthorOfPublication.8ee3c102-32cb-4eeb-a912-4fc44fbceda9

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    Genetic Evidence for Erythrocyte Receptor Glycophorin B Expression Levels Defining a Dominant Plasmodium falciparum Invasion Pathway into Human Erythrocytes
    (American Society for Microbiology, 2017) Dankwa, Selasi; Chaand, Mudit; Kanjee, Usheer; Jiang, Rays H. Y.; Nobre, Luis V.; Goldberg, Jonathan; Bei, Amy; Moechtar, Mischka A.; Gruring, Christof; Ahouidi, Ambroise D.; Ndiaye, Daouda; Dieye, Tandakha N.; Mboup, Souleymane; Weekes, Michael P.; Duraisingh, Manoj
    ABSTRACT Plasmodium falciparum, the parasite that causes the deadliest form of malaria, has evolved multiple proteins known as invasion ligands that bind to specific erythrocyte receptors to facilitate invasion of human erythrocytes. The EBA-175/glycophorin A (GPA) and Rh5/basigin ligand-receptor interactions, referred to as invasion pathways, have been the subject of intense study. In this study, we focused on the less-characterized sialic acid-containing receptors glycophorin B (GPB) and glycophorin C (GPC). Through bioinformatic analysis, we identified extensive variation in glycophorin B (GYPB) transcript levels in individuals from Benin, suggesting selection from malaria pressure. To elucidate the importance of the GPB and GPC receptors relative to the well-described EBA-175/GPA invasion pathway, we used an ex vivo erythrocyte culture system to decrease expression of GPA, GPB, or GPC via lentiviral short hairpin RNA transduction of erythroid progenitor cells, with global surface proteomic profiling. We assessed the efficiency of parasite invasion into knockdown cells using a panel of wild-type P. falciparum laboratory strains and invasion ligand knockout lines, as well as P. falciparum Senegalese clinical isolates and a short-term-culture-adapted strain. For this, we optimized an invasion assay suitable for use with small numbers of erythrocytes. We found that all laboratory strains and the majority of field strains tested were dependent on GPB expression level for invasion. The collective data suggest that the GPA and GPB receptors are of greater importance than the GPC receptor, supporting a hierarchy of erythrocyte receptor usage in P. falciparum.
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    Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria
    (Nature Publishing Group, 2016) Mantel, Pierre-Yves; Hjelmqvist, Daisy; Walch, Michael; Kharoubi-Hess, Solange; Nilsson, Sandra; Ravel, Deepali; Ribeiro, Marina; Gruring, Christof; Ma, Siyuan; Padmanabhan, Prasad; Trachtenberg, Alexander; Ankarklev, Johan; Brancucci, Nicolas M.; Huttenhower, Curtis; Duraisingh, Manoj; Ghiran, Ionita; Kuo, Winston P.; Filgueira, Luis; Martinelli, Roberta; Marti, Matthias
    Malaria remains one of the greatest public health challenges worldwide, particularly in sub-Saharan Africa. The clinical outcome of individuals infected with Plasmodium falciparum parasites depends on many factors including host systemic inflammatory responses, parasite sequestration in tissues and vascular dysfunction. Production of pro-inflammatory cytokines and chemokines promotes endothelial activation as well as recruitment and infiltration of inflammatory cells, which in turn triggers further endothelial cell activation and parasite sequestration. Inflammatory responses are triggered in part by bioactive parasite products such as hemozoin and infected red blood cell-derived extracellular vesicles (iRBC-derived EVs). Here we demonstrate that such EVs contain functional miRNA-Argonaute 2 complexes that are derived from the host RBC. Moreover, we show that EVs are efficiently internalized by endothelial cells, where the miRNA-Argonaute 2 complexes modulate target gene expression and barrier properties. Altogether, these findings provide a mechanistic link between EVs and vascular dysfunction during malaria infection.
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    Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum
    (Cell Press, 2017) Brancucci, Nicolas M.B.; Gerdt, Joseph; Wang, ChengQi; De Niz, Mariana; Philip, Nisha; Adapa, Swamy R.; Zhang, Min; Hitz, Eva; Niederwieser, Igor; Boltryk, Sylwia D.; Laffitte, Marie-Claude; Clark, Martha; Gruring, Christof; Ravel, Deepali; Blancke Soares, Alexandra; Demas, Allison; Bopp, Selina; Rubio-Ruiz, Belén; Conejo-Garcia, Ana; Wirth, Dyann; Gendaszewska-Darmach, Edyta; Duraisingh, Manoj; Adams, John H.; Voss, Till S.; Waters, Andrew P.; Jiang, Rays H.Y.; Clardy, Jon; Marti, Matthias
    Summary Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.