Are pvcrt-o and pvmdr1 Gene Mutations Associated with Plasmodium vivax Chloroquine-Resistant Parasites?

Abstract

(1) Background: Malaria remains a significant global public health issue. Since parasites quickly became resistant to most of the available antimalarial drugs, treatment effectiveness must be constantly monitored. In Brazil, up to 10% of cases of vivax malaria resistant to chloroquine (CQ) have been registered. Unlike P. falciparum, there are no definitive molecular markers for the chemoresistance of P. vivax to CQ. This work aimed to investigate whether polymorphisms in the pvcrt-o and pvmdr1 genes could be used as markers for assessing its resistance to CQ. (2) Methods: A total of 130 samples from P. vivax malaria cases with no clinical and/or parasitological evidence of CQ resistance were studied through polymerase chain reaction for gene amplification followed by target DNA sequencing. (3) Results: In the pvcrt-o exons, the K10 insert was present in 14% of the isolates. Regarding pvmdr1, T958M and F1076L haplotypes showed frequencies of 95% and 3%, respectively, while the SNP Y976F was not detected. (4) Conclusions: Since K10-pvcrt-o and F1076L/T958M-pvmdr1 polymorphisms were detected in samples from patients who responded well to CQ treatment, it can be concluded that mutations in these genes do not seem to have a potential for association with the phenotype of CQ resistance.

Keywords: P. vivax; chemoresistance; chloroquine; malaria; pvcrt-o; pvmdr1.

Figure 1

Brazilian map highlighting the Acre (AC), Amazonas (AM), Amapá (AP), Pará (PA), Rondônia (RO) and Roraima (RR) states and the municipalities of parasite infection.

Figure 2

Alignment of representative CQ-resistant and -sensitive pvcrt-o sequences, with the K10 insertion highlighted in red. Melo R1 to R12 correspond to CQ-resistant sequences of Melo et al. [20]. The sequences named K10 01 to 31 correspond to the isolates sequenced in this study. AC: Acre; AM: Amazonas; AP: Amapá; PA: Pará; RO: Rondônia; RR: Roraima.

Figure 3

Alignment of representative CQ-resistant and -sensitive pvmdr1 sequences, with the SNPs investigated highlighted in red (T958M, Y976F and F1076L). Melo R1 to R12 correspond to CQ-resistant sequences of Melo et al. [20]. The sequences named TYF correspond to the isolates with the wild-type haplotype sequenced in this study. Sequences named MYL and MYF correspond to the isolates with one and two non-synonymous mutations detected in this study, respectively. AC: Acre; AM: Amazonas; AP: Amapá; PA: Pará; RO: Rondônia; RR: Roraima.