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Infections with  Plasmodium falciparum,  the most pathogenic of the  Plasmodium  species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR)  P. falciparum  Thai C2A parasite strain in the non-human  Aotus  primate model, and across multiple passages.  Aotus  infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and  ex vivo  drug assays demonstrated reduction in drug susceptibility profiles in later  Aotus  passages. Further analysis revealed mutations in the  pfcrt  and  pfdhfr  loci and increased parasite multiplication rate (PMR) across passages, despite elevated  pfmdr1  copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during  Aotus  adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant  P. falciparum  Thai isolate in this animal model.

Altered drug susceptibility during host adaptation of a Plasmodium falciparum strain in a non-human primate model