ORCID Profile
0000-0003-2947-5651
Current Organisation
Kumasi Centre for Collaborative Research in Tropical Medicine
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Publisher: Springer Science and Business Media LLC
Date: 25-01-2017
DOI: 10.1038/NATURE21038
Publisher: Cold Spring Harbor Laboratory
Date: 13-05-2022
DOI: 10.1101/2022.05.13.491767
Abstract: Reduced susceptibility to ART, the first-line treatment against malaria, is common in South East Asia (SEA). It is caused by point mutations, mostly in kelch13 ( k13 ) but also in other genes, like upb1 . 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 of k13 C580Y with k13 R539T or k13 C580Y with ubp1 R3138H, did also not increase resistance. In contrast, k13 C580Y parasites subjected to consecutive RSAs did, but the k13 sequence was not altered. Using isogenic parasites with different k13 mutations, 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 of k13 mutations correlated with ART resistance, ubp1 R3138H caused a disproportionately higher fitness cost. ART 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 in k13 , including the two most common resistance mutations in SEA, or with non- k13 genes, are a threat to lead to higher resistance. However, repeated ART exposure increased resistance by mechanisms not altering k13 gene sequence, indicating changes in the background of these parasites. The disproportionally high fitness cost of ubp1 R3138H may explain why kic mutations affecting resistance are rare and highlights the unique property of K13 to influence endocytosis only in ring stages.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2019
Location: Ghana
No related grants have been discovered for Oumou Maiga Ascofare.