Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility
Issued Date
2024-12-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-85213687538
Journal Title
Nature Communications
Volume
15
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Communications Vol.15 No.1 (2024)
Suggested Citation
Ibrahim A., Mohring F., Manko E., van Schalkwyk D.A., Phelan J.E., Nolder D., Borrmann S., Adegnika A.A., Di Santi S.M., Alam M.S., Mondal D., Nosten F., Sutherland C.J., Moon R.W., Clark T.G., Campino S. Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility. Nature Communications Vol.15 No.1 (2024). doi:10.1038/s41467-024-55102-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/102640
Title
Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility
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Abstract
Plasmodium malariae parasites are widely observed across the tropics and sub-tropics. This slow-growing species, known to maintain chronic asymptomatic infections, has been associated with reduced antimalarial susceptibility. We analyse 251 P. malariae genomes from 28 countries, and leveraging 131,601 high-quality SNPs, demonstrate segregation of African and Asian isolates. Signals of recent evolutionary selection were identified in genes encoding putative surface proteins (pmmsp1) and putative erythrocyte invasion proteins (pmdpap3, pmrbp2, pmnif4). Amino acid substitutions were identified in orthologs of genes associated with antimalarial susceptibility including 2 amino acid substitutions in pmdhfr aligning with pyrimethamine resistance mutations in P. falciparum. Additionally, we characterise pmdhfr mutation F57L and demonstrate its involvement in reduced susceptibility to pyrimethamine in an in vitro parasite assay. We validate CRISPR-Cas9 mediated ortholog replacement in P. knowlesi parasites to determine the function of pmdhfr mutations and demonstrate that circulating pmdhfr genotypes are less susceptible to pyrimethamine.