Association of pfcrt But Not pfmdr1 Alleles with Chloroquine Resistance in Iranian Isolates of Plasmodium falciparum

Abstract

This study was designed to analyze the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) mutations as markers of chloroquine (CQ) resistance in 200 blood samples collected from malaria patients in south-eastern Iran during 2002-2005. Among these, 25 (post-treatment) fulfilled the 28-day follow-up study. A high number of Iranian P. falciparum (97%) strains harbored quadruple mutations at codons 76T, 220S, 326D, and 356L. All post-treatment isolates harbored the mutant allele 76T, but low rates of the mutant allele 86Y (44%) of the pfmdr1 gene were detected. No wild haplotype of pfcrt (72-CVMNKAQNIR-371) was found in post-treatment samples; however, 56% of clinical "failure" samples carried the wild type of pfmdr1 (NYSND). The present results suggest a strong association between pfcrt 76T, but not pfmdr1 86Y mutation and in vivo CQ resistance. Furthermore, we found the CQ resistance-associated SVMNT haplotype, which previously had been seen in South American isolates. Although Iran is located more proximally to Southeast Asia than to South America, no CQ resistance-associated CVIET haplotye has been observed in this region. Therefore, these results were not consistent with the earlier presumed spread of CQR parasites from Southeast Asia to Africa via the Indian subcontinent. In conclusion, P. falciparum mutations associated with resistance to CQ are abundant in south-eastern Iran and this finding strongly supports that CQ as the first line drug is inadequate for treatment of uncomplicated falciparum malaria in Iran.

Distribution of Drug Resistance Genotypes in Plasmodium falciparum in an Area of Limited Parasite Diversity in Saudi Arabia

“…Therefore, the current use of ACT in Jazan may be exerting a novel pressure on the local parasites to select for alleles Pfmdr1 86N 184F 1246D and Pfcrt-74M 75N 76K, 53 some of which are currently rare in Saudi Arabia; however, the wildtype pfmdr1-1246D is at fixation, and the mutant form was not seen in neighboring countries such as Iran. 54,55 Whether the prevalence of the wild-type Pfmdr1 mutations will change under increasing artemisnin pressure will be of considerable interest in the future. However, currently, the apparent effectiveness of SP should protect artemisinin and reduce effective selective pressure.…”

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

“…One likely influence is the history of AQ and CQ use in these regions and the consequent selective pressure for pfcrt and pfmdr1 polymorphisms of one type or another. Haplotypes of pfcrt-encoding polymorphisms similar to those of the pfcrt alleles in South America and PNG have been reported from East Timor, Indonesia, the Philippines, Laos, India, and Iran (40)(41)(42)(43)(44)(45)(46)(47)(48)(49). In many of these regions AQ was widely used in the 1940s (50) and early 1950s before the advent of CQR (Fig.…”

The impact of malaria parasitism: from corpuscles to communities

“…PfCRT molecules from the individual foci all contain a key K76T amino-acid replacement but are distinguished by different patterns of accompanying codon polymorphisms and chromosome haplotype polymorphisms. In addition to five foci previously depicted (109), the map indicates recently described parasites in India and Iran that probably spread from an additional focus of chloroquine resistance (122,123). tant components of the malaria experience that leads to eventual acquisition of disease-controlling immunity.…”