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ISBN : 978-2-4061-5830-

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ISBN : 978-2-4061-5830-

Navigation

ISBN : 978-2-4061-5830-

Navigation

ISBN : 978-2-4061-5830-

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ISBN : 978-2-4061-5830-

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ISBN : 978-2-4061-5830-

Impact of different mutations on Kelch13 protein levels, ART resistance and fitness cost in<i>Plasmodium falciparum</i>parasites

AbstractReduced susceptibility to ART, the first-line treatment against malaria, is common in South East Asia (SEA). It is caused by point mutations, mostly inkelch13(k13) but also in other genes, likeupb1. K13 and its compartment neighbors (KICs), including UBP1, are involved in endocytosis of host cell cytosol. We tested 135 mutations in KICs but none conferred ART resistance. Double mutations ofk13C580Y withk13R539T ork13C580Y withubp1R3138H, did also not increase resistance. In contrast,k13C580Y parasites subjected to consecutive RSAs did, but thek13sequence was not altered. Using isogenic parasites with differentk13mutations, we found correlations between K13 protein amount, resistance and fitness cost. Titration of K13 and KIC7 indicated that the cellular levels of these proteins determined resistance through the rate of endocytosis. While fitness cost ofk13mutations correlated with ART resistance,ubp1R3138H caused a disproportionately higher fitness cost.SignificanceART resistance is only a partial resistance with a proportion of ring stages surviving physiological ART levels. The correlation of resistance with fitness cost in isogenic lines indicates that fitness cost likely prevents resistance levels permitting survival of all ring stages under physiological ART concentrations. We also found no indication that double mutations ink13, including the two most common resistance mutations in SEA, or with non-k13genes, are a threat to lead to higher resistance. However, repeated ART exposure increased resistance by mechanisms not alteringk13gene sequence, indicating changes in the background of these parasites. The disproportionally high fitness cost ofubp1R3138H may explain whykicmutations affecting resistance are rare and highlights the unique property of K13 to influence endocytosis only in ring stages.</jats:sec

Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial

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