Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility

Amy Ibrahim, Franziska Mohring, Emilia Manko, Donelly A. Schalkwyk, Jody E. Phelan, Debbie Nolder, Steffen Borrmann, Ayola A. Adegnika, Silvia Maria Santi, Mohammad Shafiul Alam, Dinesh Mondal, Francois Nosten, Colin J. Sutherland, Robert W. Moon (), Taane G. Clark () and Susana Campino ()
Additional contact information
Amy Ibrahim: London School of Hygiene & Tropical Medicine
Franziska Mohring: London School of Hygiene & Tropical Medicine
Emilia Manko: London School of Hygiene & Tropical Medicine
Donelly A. Schalkwyk: London School of Hygiene & Tropical Medicine
Jody E. Phelan: London School of Hygiene & Tropical Medicine
Debbie Nolder: London School of Hygiene & Tropical Medicine
Steffen Borrmann: Gabon; and German Center for Infection Research (DZIF)
Ayola A. Adegnika: Gabon; and German Center for Infection Research (DZIF)
Silvia Maria Santi: University of São Paulo
Mohammad Shafiul Alam: International Centre for Diarrhoeal Disease Research Bangladesh
Dinesh Mondal: International Centre for Diarrhoeal Disease Research Bangladesh
Francois Nosten: Mahidol University
Colin J. Sutherland: London School of Hygiene & Tropical Medicine
Robert W. Moon: London School of Hygiene & Tropical Medicine
Taane G. Clark: London School of Hygiene & Tropical Medicine
Susana Campino: London School of Hygiene & Tropical Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-55102-3

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