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

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.

The human malaria- Aotus monkey model: a historical perspective in antimalarial chemotherapy research at the Gorgas Memorial Laboratory-Panama

“…Still, its neurologic side effects (psychiatric effects that could last years after use) limit its full potential ( 36 ). Nevertheless, today, it is being used alone or in combination with QHS derivatives as an effective ACT, except for areas of Southeast Asia, where MQ resistance is prevalent ( 107 ).…”

“…Eventually, oral ACTs entered into clinical trials and were adopted as the first-line treatment for uncomplicated malaria by WHO in 2006 ( 108 , 110 ), while parenteral i.v. AS was indicated for severe, complicated malaria ( 107 ). By 2009, decreased susceptibility to AS was reported in western Cambodia, and since then, it has spread to the rest of Southeast Asia ( 107 ).…”

“…AS was indicated for severe, complicated malaria ( 107 ). By 2009, decreased susceptibility to AS was reported in western Cambodia, and since then, it has spread to the rest of Southeast Asia ( 107 ).…”

“…Intrigued by the decreased susceptibility to AS observed during the adaptation of the MDR Thai P. falciparum C2A strain when administered orally to Aotus at 33 mg/kg per 3 days, Obaldia et al ( 107 ) investigated the efficacy of AS alone or in combination with MQ in six splenectomized Aotus monkeys. This study aimed to rule out the inoculum size effect (high vs low) reported by others during QHS susceptibility testing in laboratory strains in vitro ( 114 ).…”

“…In these experiments, the animals were infected with a high Aotus passage (passage X) of the MDR Thai P. falciparum C2A clone, using a standard inoculum of 5 × 10 6 parasites. This clone was isolated from a patient in a Thailand hospital in 1992, before the advent of QHS resistance in Southeast Asia ( 107 ). The MDR Thai Aotus -adapted P. falciparum C2A clone demonstrated resistance to orally administered MQ at doses as high as 40 mg/kg once and AS at 33 mg/kg per 3 days (fourfold higher than that needed to clear P. falciparum FVO infections in Aotus ) alone or in combination and comparable to in vitro data obtained from parasites during adaptation ( Table 1 ) ( 71 , 107 ).…”