Genetic architecture of artemisinin-resistant Plasmodium falciparum

Abstract

We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.

Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters

“…Single nucleotide polymorphism (SNP) in Pfcrt (codon 76) is associated with CQ and AQ resistance in P. falciparum ( Ecker et al , 2012; Fidock et al , 2000; Ochong et al , 2003). Recent studies also identified potential crt background mutations; Ile356Thr and Asn326Ser that associate with artemisinin resistance ( Miotto et al, 2015). In the present study, nucleotide codons corresponding to amino acid position 76, 326 and 356 of the PbCRT protein were found not to harbour any mutation in AQ resistant line (compared to sensitive line).…”

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

“…Additional investigation is required to determine if these adaptive signatures are geographically restricted (68) or occurred as or before P. vivax expanded out of Africa. In the case of P. falciparum, reductions in diversity immediately around loci associated with drug resistance (73,74) are commonly reported, and the current substructuring seen in Cambodian P. falciparum parasites has been linked to drugresistant subtypes (22). This evidence suggests that more recent selective forces have shaped population structure in this species.…”

“…The population structure of P. falciparum in Cambodia has been shaped by the intensive use of artemisinins and their partner drugs, bed nets, and improved diagnostics (21,22). However, little is known about how coendemic P. vivax populations have responded to these same selective forces.…”

Malaria Genomics in the Era of Eradication

“…Such work illuminated the recent demographic history of multiple parasite and vector species, defined sometimes complex gene flow boundaries, and revealed the impact of immune, drug, or insecticide selection on the genomes of malaria parasites and vectors. Subsequently, more comprehensive characterizations of genetic diversity have yielded thorough inventories of genomic diversity across many geographic regions (Amambua-Ngwa et al 2012;Manske et al 2012;Miotto et al 2013Miotto et al , 2015 MalariaGEN P. falciparum Community Project 2016), refining our understanding of population boundaries and diversity differences between populations. Collectively, this deep genomic sequencing dataset, for example, represented in the open-access Pf3k collaboration and database (www.malariagen.net/projects/ pf3k), facilitates informed development of markers for genotyping to analyze even larger sample collections.…”