Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Abstract

In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. malaria | drug resistance | evolution | Plasmodium falciparum | PfCRT

Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

“…Polymorphisms in addition to those commonly described in African isolates have been identified in other regions, in some cases with biochemical and clinical consequences (49,50). Sequencing of pfcrt in a subset of samples either under or not under the selective pressure of DP identified a few previously unidentified pfcrt mutations, but it did not suggest that additional polymorphisms were selected by DP.…”

Molecular Profile of Malaria Drug Resistance Markers of Plasmodium falciparum in Suriname

“…However, the potential role of background mutations and their association with artemisinin resistance needs further validation in South America. Additionally, most of the Suriname samples (62%) had the PfCRT C350R mutation, which has been associated with a CQ phenotypic reversion and a strong piperaquine drug-selective pressure (5). Given that gold miners living in the forest are known to self-medicate with dihydroartemisinin-piperaquine-trimethoprim tablets, it is not surprising that this PfCRT mutation is found in high frequency in these study samples, especially if we consider that 87% of the patients came from artisanal gold mining areas in French Guiana.…”

Plasmodium falciparum Resistance to Artemisinin Derivatives and Piperaquine: A Major Challenge for Malaria Elimination in Cambodia

“…82,90 For instance, isolates containing parasites with a variant of the Dd2 Pfcrt allele carrying either 97Y, 343L, or 353V have higher median PSA survival rates than those harboring the Dd2 allele. 82 In French Guiana, Pelleau and others also found that the acquisition of the C350R substitution in the Pfcrt gene decreased susceptibility to PPQ, suggesting that PPQ pressure drove the expansion of this allele.…”

“…82 In French Guiana, Pelleau and others also found that the acquisition of the C350R substitution in the Pfcrt gene decreased susceptibility to PPQ, suggesting that PPQ pressure drove the expansion of this allele. 90 As the 353V mutation (frequently observed in Cambodia) is located close to 350R, further investigations, such as genome editing, should be carried out to assess the role of Pfcrt mutations in the genetic background of Cambodian parasites.…”