Abstract
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.
Highlights
Demonstrated presence of quadruple-mutations in the dhfr-thymidylate synthase gene[10] and increased pfmdr[1] copy number[11]
QHS monotherapy had been used in western Cambodia since the late 1970’s and MQ was introduced in Thailand in 19843
Malaria naive and splenectomized male and female Aotus lemurinus lemurinus monkeys were inoculated with 5 × 106 parasites of the C2A clone on its IX serial passage from a donor Aotus and further divided into three oral treatment groups of two monkeys each (Fig. 1, Table 1): one group was treated with a single dose of 40 mg/Kg of oral MQ; a second group was treated with daily doses of 33 mg/Kg of oral AS for three days; and a third group was treated with a combination of a single dose of oral MQ and three daily doses of oral AS
Summary
Demonstrated presence of quadruple-mutations in the dhfr-thymidylate synthase gene[10] and increased pfmdr[1] copy number[11]. This combination of mutations and pfmdr[1] copy number variation (CNV) has been associated in field isolates with higher in vitro inhibitory concentrations to MQ, quinine (QN), halofantrine and QHS, and with failure of MQ monotherapy and AS/MQ combination therapy at the Thai-Cambodian border[12,13]. We reported the adaptation of the Thai C2A clone to splenectomized Aotus l. To determine the basis for the altered drug sensitivity phenotype during Aotus adaptation, we tested the antimalarial drug efficacy to MQ and artemisinin derivatives in vivo and in vitro in C2A, and correlated these parameters with growth rates, genotypic changes and mutations in antimalarial drug resistance genes
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