Expression Levels of pvcrt-o and pvmdr-1 Are Associated with Chloroquine Resistance and Severe Plasmodium vivax Malaria in Patients of the Brazilian Amazon

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.

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

“…Histone deacetylase inhibitors accelerated the rate of hypnozoite activation in long-term primary simian hepatocyte cultures, suggesting that histone methylation may maintain hypnozoite dormancy by suppressing transcription (42,43). Finally, P. vivax chloroquine resistance has not been found to correlate with DNA changes in pvcrt but may correlate with the expression of this transporter protein, whose ortholog mediates chloroquine resistance in P. falciparum (44)(45)(46).…”

Mapping malaria in municipalities of the Coffee Triangle region of Colombia using Geographic Information Systems (GIS)

“…In this tropical epidemiological scenario, clinical studies addressing that topic would also be useful, given that few studies in the country have assessed the epidemiology of severe P. vivax malaria [11,32], which has been largely documented and reported in other countries of Latin America, such as Venezuela [33][34][35] and Brazil [36][37][38], as well in Asia [39][40][41].…”

Metabolome-wide association study of peripheral parasitemia in Plasmodium vivax malaria

“…In this study, we used retrospective plasma samples obtained from patients with P. vivax malaria at the Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD), as reported previously (Melo et al, 2014; Siqueira et al, 2015). Plasma samples were obtained under standard laboratorial procedures and stored at −80 ºC.…”

“…Briefly, all patients underwent an initial clinical characterization and physical examination followed by antimalarial treatment according to appropriate guidelines. At admission, laboratorial evaluation consisted of full blood count and biochemical analyses (hemoglobin, alanine aminotransferase, aspartate aminotransferase and creatinine), as reported (Melo et al, 2014; Siqueira et al, 2015). Diagnosis and quantification of parasitemia were performed with thick blood smear (TBS) microscopy.…”

“…Parasitemia was determined by the mean of two readings of parasites and the white blood cell counts from total blood. Mono-infections with P. vivax were confirmed by PCR (Melo et al, 2014; Siqueira et al, 2015). Patients were classified into three categories of parasitemia: low (10–999 parasites/μL), moderate (1,000–9,999 parasites/μL) and high (> 10,000 parasites/μL) according to previous studies (Ketema and Bacha, 2013; Kotepui et al, 2015).…”