Global distribution of polymorphisms associated with delayed Plasmodium falciparum parasite clearance following artemisinin treatment: Genotyping of archive blood samples

Abstract

The recent emergence and spread of artemisinin-resistant Plasmodium falciparum isolates is a growing concern for global malaria-control efforts. A recent genome-wide analysis study identified two SNPs at genomic positions MAL10-688956 and MAL13-1718319, which are linked to delayed clearance of parasites following artemisinin combination therapy (ACT). It is expected that continuous artemisinin pressure will affect the distribution of these SNPs. Here, we investigate the worldwide distribution of these SNPs using a large number of archived samples in order to generate baseline data from the period before the emergence of ACT resistance. The presence of SNPs in MAL10-688956 and MAL13-1718319 was assessed by nested PCR RFLP and direct DNA sequencing using 653 global P. falciparum samples obtained before the reported emergence of ACT resistance. SNPs at MAL10-688956 and MAL13-1718319 associated with delayed parasite clearance following ACT administration were observed in 8% and 3% of parasites, respectively, mostly in Cambodia and Thailand. Parasites harbouring both SNPs were found in only eight (1%) isolates, all of which were from Cambodia and Thailand. Linkage disequilibrium was detected between MAL10-688956 and MAL13-1718319, suggesting that this SNP combination may have been selected by ACT drug pressure. Neither of the SNPs associated with delayed parasite clearance were observed in samples from Africa or South America. Baseline information of the geographical difference of MAL10-688956 and MAL13-1718319 SNPs provides a solid basis for assessing whether these SNPs are selected by artemisinin-based combination therapies.

Malaria epidemiological research in the Republic of Congo

“…A total of eight articles have been found reporting data on molecular markers of P. falciparum resistance to anti-malarials with samples collected from 1999 to 2015 [11, 15, 23–25, 31, 32, 36]. Overall, six molecular markers have been studied: the P. falciparum chloroquine resistance transporter ( pfcrt ) gene, associated with chloroquine resistance, the dihydrofolate reductase ( dhfr ) and the dihydropteroate synthase ( dhps ) genes, which are linked with pyrimethamine resistance and sulfadoxine resistance, respectively, the P. falciparum Klech-13 (K13) propeller gene, which has recently been linked with artemisinin resistance, and MAL10-688956 and MAL13-1718319 single nucleotide polymorphisms (SNPs) which have also recently been proposed as molecular markers of artemisinin resistance which is defined as a delayed clearance of P. falciparum parasites following ACT.…”

“…The K13 propeller gene was characterized by Mita et al [32], and MAL10-688956 and MAL13-1718319 SNPs have been characterized by Murai et al [31]. In both studies they used the same set of archived P. falciparum isolates collected in 2005–2006 in Brazzaville, Pointe-Noire and Gamboma, and none of the mutations associated with artemisinin resistance was found.…”

High-level artemisinin-resistance with quinine co-resistance emerges in P. falciparum malaria under in vivo artesunate pressure

“…Thus, we are now faced with a number of kelch-13 mutant alleles of uncertain clinical significance. On the other hand, SNPs in RAD5 are extremely rare outside Asia [ 70 ], yet one was selected for in our parasites of African origin under ART pressure.…”

A mosquito sperm's journey from male ejaculate to egg: Mechanisms, molecules, and methods for exploration

“…Aedes aegypti and Aedes albopictus transmit dengue viruses, which cause more than 100 million infections (Bhatt et al, 2013), as well as emerging viral threats such as chikungunya (Staples and Fischer, 2014) and Zika (Fauci and Morens, 2016). Many mosquitoborne pathogens have no commercially licensed vaccine or cure; even for those with a cure, such as malaria, drug resistance poses a serious challenge (Murai et al, 2015). The most effective tools against mosquito-borne pathogens therefore remain those focused on regulating vector populations.…”