Background: Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001-2014).
Results: We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance.
Conclusions: This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.
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http://dx.doi.org/10.1186/s13059-017-1204-4 | DOI Listing |
New Microbes New Infect
December 2024
Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Amsterdam University Medical Centers, Location AMC, Amsterdam Infection & Immunity, Amsterdam Public Health, University of Amsterdam, Amsterdam, the Netherlands.
Background: Accurate scientific terminology is crucial in health sciences to avoid misinterpretations. The use of 'artemisinin resistance' to describe delayed parasite clearance may be inaccurately equated with full resistance, as is typically the case when 'resistance' is used with other pathogens, leading to potential confusion. In 2018, the World Health Organization (WHO) introduced 'partial artemisinin resistance' to more accurately reflect the delayed parasite clearance observed with artemisinin-based therapies.
View Article and Find Full Text PDFLancet Infect Dis
December 2024
MMV Medicines for Malaria Venture, Geneva, Switzerland.
Background: Novel antimalarials are needed to address emerging resistance to artemisinin and partner drugs. We did two trials to evaluate safety, tolerability, pharmacokinetics, and activity against blood stage Plasmodium falciparum for the drug candidate MMV533.
Methods: A phase 1a first-in-human (FIH) trial was conducted at Nucleus Network (Melbourne, VIC, Australia).
Lancet Microbe
December 2024
Malaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
Background: Triple artemisinin-based combination therapies (TACTs) can delay the spread of antimalarial drug resistance. Artesunate-amodiaquine is widely used for uncomplicated Plasmodium falciparum malaria. We therefore aimed to determine the safety and efficacy of artemether-lumefantrine-amodiaquine and artesunate-amodiaquine with and without single low-dose primaquine for reducing gametocyte carriage and transmission to mosquitoes.
View Article and Find Full Text PDFAntimicrob Agents Chemother
December 2024
Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.
Praziquantel alone is insufficient for the control of schistosomiasis due to poor efficacy against juvenile worms and increasing concerns about the risk of drug resistance. We compared the efficacy and safety of praziquantel combined with four different artemisinin-based combinations to praziquantel alone in treating infection in Kenyan children. In this randomized, open-label, five-arm, head-to-head, non-inferiority trial, children (aged 9-15 years) with infection according to duplicate Kato Katz thick smears from a stool sample in the Mwea irrigation scheme of central Kenya, were enrolled.
View Article and Find Full Text PDFMalar J
December 2024
Malaria Research and Training Center, Faculty of Pharmacy, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
Background: Malaria remains a significant public health concern, despite global efforts to combat the disease with highest burden in Africa. Reports of emerging artemisinin partial- resistance in East Africa emphasize the importance of molecular data to guide policy decisions. Hence the need for researchers to collaborate with National control programmes to conduct genomics surveillance of malaria to inform malaria control and elimination policies.
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