Abstract
Molecular markers associated with the increase of chloroquine resistance and disease severity in Plasmodium vivax are needed. The objective of this study was to evaluate the expression levels of pvcrt-o and pvmdr-1 genes in a group of patients presenting CQRPv and patients who developed severe complications triggered exclusively by P. vivax infection. Two different sets of patients were included to this comprehensive study performed in the Brazilian Amazon: 1) patients with clinically characterized chloroquine-resistant P. vivax compared with patients with susceptible parasites from in vivo studies and 2) patients with severe vivax malaria compared with patients without severity. Quantitative real-time PCR was performed to compare the transcript levels of two main transporters genes, P. vivax chloroquine resistance transporter (pvcrt-o) and the P. vivax multidrug resistance transporter (pvmdr-1). Twelve chloroquine resistant cases and other 15 isolates from susceptible cases were included in the first set of patients. For the second set, seven patients with P. vivax-attributed severe and 10 mild manifestations were included. Parasites from patients with chloroquine resistance presented up to 6.1 (95% CI: 3.8–14.3) and 2.4 (95% CI: 0.53–9.1) fold increase in pvcrt-o and pvmdr-1 expression levels, respectively, compared to the susceptible group. Parasites from the severe vivax group had a 2.9 (95% CI: 1.1–8.3) and 4.9 (95% CI: 2.3–18.8) fold increase in pvcrt-o and pvmdr-1 expression levels as compared to the control group with mild disease. These findings suggest that chloroquine resistance and clinical severity in P. vivax infections are strongly associated with increased expression levels of the pvcrt-o and pvmdr-1 genes likely involved in chloroquine resistance.
Highlights
Mechanisms underlying severe malaria triggered by Plasmodium vivax have been poorly appreciated, mainly the likely higher and more-severe disease burden imposed by increasingly chloroquine-resistant P. vivax parasites (CQRPv) [1,2]
Expression levels of pvcrt-o and pvmdr-1 genes were determined in patients with CQRPv from a well-characterized cohort under supervised treatment, pointing to a link between in vivo CQR and overexpression of both genes
These patients showed higher concentrations of CQ and microsatellite revealed the presence of the same clonal nature at D0 and Day of recrudescence (DR), bringing evidence that the re-emergent infection is the same as the primary infection, indicating recrudescence
Summary
Mechanisms underlying severe malaria triggered by Plasmodium vivax have been poorly appreciated, mainly the likely higher and more-severe disease burden imposed by increasingly chloroquine-resistant P. vivax parasites (CQRPv) [1,2]. The majority of reports on severe vivax malaria come from regions where drug-resistant P. vivax parasites significantly thread the radical cure and control of this infection [5]. In Brazil, the first case of properly ascertained in vivo CQRPv was from a patient treated in Manaus, in the Brazilian Amazon [8]. In this city, a subsequent trial assessed the efficacy of standard supervised CQ monotherapy and the proportion of failures was 10.1% [9]. In parallel to the emergence of CQRPv in the Brazilian Amazon, reports of clinical severity exclusively associated with P. vivax infection increased substantially [3,10,11,12]
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