Limited Polymorphism of the Kelch Propeller Domain in Plasmodium malariae and P. ovale Isolates from Thailand.

Supatchara Nakeesathit,Arjen Dondorp,Nicholas J White,Naowarat Saralamba,Sasithon Pukrittayakamee,Francois Nosten,Mallika Imwong

doi:10.1128/aac.00138-16

Abstract

Artemisinin resistance in Plasmodium falciparum, the agent of severe malaria, is currently a major obstacle to malaria control in Southeast Asia. A gene named “kelch13” has been associated with artemisinin resistance in P. falciparum. The orthologue of the kelch gene in P. vivax was identified and a small number of mutations were found in previous studies. The kelch orthologues in the other two human malaria parasites, P. malariae and P. ovale, have not yet been studied. Therefore, in this study, the orthologous kelch genes of P. malariae, P. ovale wallikeri, and P. ovale curtisi were isolated and analyzed for the first time. The homologies of the kelch genes of P. malariae and P. ovale were 84.8% and 82.7%, respectively, compared to the gene in P. falciparum. kelch polymorphisms were studied in 13 P. malariae and 5 P. ovale isolates from Thailand. There were 2 nonsynonymous mutations found in these samples. One mutation was P533L, which was found in 1 of 13 P. malariae isolates, and the other was K137R, found in 1 isolate of P. ovale wallikeri (n = 4). This result needs to be considered in the context of widespread artemisinin used within the region; their functional consequences for artemisinin sensitivity in P. malariae and P. ovale will need to be elucidated.

Highlights

Artemisinin resistance in Plasmodium falciparum, the agent of severe malaria, is currently a major obstacle to malaria control in Southeast Asia
Malaria is caused by protozoa of the genus Plasmodium, with the following five species causing disease in humans: Plasmodium falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi
Because P. malariae and P. ovale are frequently found as mixed infections with P. falciparum, these species are exposed to Artemisinin-based combination therapies (ACTs) when P. falciparum infections are being treated

Summary

Introduction

Artemisinin resistance in Plasmodium falciparum, the agent of severe malaria, is currently a major obstacle to malaria control in Southeast Asia. P. malariae is the third most common infecting species, with incidences in areas of endemicity reported to be Ͻ4% to 20% of the total number of malaria infections [2] This parasite has a 72-h erythrocytic developmental cycle and is usually detected at low parasitemias in mixed infections with either P. falciparum or P. vivax. The original studies reported the K13 propeller mutations C580Y, R539T, and Y493H in Cambodian P. falciparum strains, and interestingly, only one mutation per kelch gene seemed to be allowed [5] Since these initial studies, more than 60 single nucleotide polymorphisms (SNPs) in the K13 propeller have been identified, of which most correlate with the slow-clearance phenotype [6]. Among Cambodian P. vivax strains, a V552I polymorphism in the orthologous kelch gene has been described for two isolates [7] It is not known whether this mutation in P. vivax causes resistance to artemisinins.

Methods

Results

Conclusion