Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility
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 leverag...
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2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55102-3 |
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| author | Amy Ibrahim Franziska Mohring Emilia Manko Donelly A. van Schalkwyk Jody E. Phelan Debbie Nolder Steffen Borrmann Ayola A. Adegnika Silvia Maria Di Santi Mohammad Shafiul Alam Dinesh Mondal Francois Nosten Colin J. Sutherland Robert W. Moon Taane G. Clark Susana Campino |
| author_facet | Amy Ibrahim Franziska Mohring Emilia Manko Donelly A. van Schalkwyk Jody E. Phelan Debbie Nolder Steffen Borrmann Ayola A. Adegnika Silvia Maria Di Santi Mohammad Shafiul Alam Dinesh Mondal Francois Nosten Colin J. Sutherland Robert W. Moon Taane G. Clark Susana Campino |
| author_sort | Amy Ibrahim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-76df5cef751540ac9ba3f28eb89a9988 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-76df5cef751540ac9ba3f28eb89a99882025-01-05T12:36:11ZengNature PortfolioNature Communications2041-17232024-12-0115111210.1038/s41467-024-55102-3Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibilityAmy Ibrahim0Franziska Mohring1Emilia Manko2Donelly A. van Schalkwyk3Jody E. Phelan4Debbie Nolder5Steffen Borrmann6Ayola A. Adegnika7Silvia Maria Di Santi8Mohammad Shafiul Alam9Dinesh Mondal10Francois Nosten11Colin J. Sutherland12Robert W. Moon13Taane G. Clark14Susana Campino15Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineInstitute for Tropical Medicine, Eberhard Karls University of Tübingen, Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, Gabon; and German Center for Infection Research (DZIF)Institute for Tropical Medicine, Eberhard Karls University of Tübingen, Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, Gabon; and German Center for Infection Research (DZIF)School of Medicine, University of São PauloInternational Centre for Diarrhoeal Disease Research BangladeshInternational Centre for Diarrhoeal Disease Research BangladeshShoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol UniversityFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineFaculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical MedicineAbstract 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.https://doi.org/10.1038/s41467-024-55102-3 |
| spellingShingle | Amy Ibrahim Franziska Mohring Emilia Manko Donelly A. van Schalkwyk Jody E. Phelan Debbie Nolder Steffen Borrmann Ayola A. Adegnika Silvia Maria Di Santi Mohammad Shafiul Alam Dinesh Mondal Francois Nosten Colin J. Sutherland Robert W. Moon Taane G. Clark Susana Campino Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility Nature Communications |
| title | Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility |
| title_full | Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility |
| title_fullStr | Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility |
| title_full_unstemmed | Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility |
| title_short | Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility |
| title_sort | genome sequencing of plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility |
| url | https://doi.org/10.1038/s41467-024-55102-3 |
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