{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:55:31Z","timestamp":1791046531518,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,7]]},"group-title":"Microbiology","reference-count":30,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["INV-003442"],"award-info":[{"award-number":["INV-003442"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["INV-019032"],"award-info":[{"award-number":["INV-019032"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["INV-049909"],"award-info":[{"award-number":["INV-049909"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["INV-101391"],"award-info":[{"award-number":["INV-101391"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute Health, USA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Artemisinin-based combination therapies are the frontline treatment for\n                  <jats:italic>Plasmodium falciparum<\/jats:italic>\n                  malaria, but their efficacy is threatened by Artemisinin partial resistance (ART\n                  <jats:sup>R<\/jats:sup>\n                  ). ART\n                  <jats:sup>R<\/jats:sup>\n                  in\n                  <jats:italic>Plasmodium falciparum<\/jats:italic>\n                  is mediated by\n                  <jats:italic>Pfkelch13<\/jats:italic>\n                  (\n                  <jats:italic>k13<\/jats:italic>\n                  ) mutations but remains rare in West Africa. A critical question is whether short-term drug survival intrinsically predicts long-term evolutionary persistence. Here, using CRISPR-Cas9 editing, and nanopore-assisted allele tracking in a contemporary Senegalese isolate, we evaluated ART\n                  <jats:sup>R<\/jats:sup>\n                  receptivity using the ring-stage survival assay (RSA), a proxy for clinical resistance. We demonstrate that ART\n                  <jats:sup>R<\/jats:sup>\n                  survival and drug-free persistence are biologically separable traits. While the WHO-validated Asian I543T mutation conferred the RSA phenotype, it was rapidly counter-selected during drug-free growth. In contrast, emerging African alleles (R561H, M579I) and a regional novel variant (C473S) establish stable resistance without a competitive penalty. These findings reveal that a parasite\u2019s genetic background acts as a strict evolutionary filter, uncoupling short-term tolerance from long-term persistence and establishing that genomic context determines allele-specific resistance trajectories.\n                <\/jats:p>","DOI":"10.64898\/2026.09.03.749253","type":"posted-content","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T04:40:10Z","timestamp":1788842410000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic background determines allele-specific\n                  <i>Pfkelch13<\/i>\n                  -mediated artemisinin tolerance and persistence in\n                  <i>Plasmodium falciparum<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1432-1705","authenticated-orcid":false,"given":"Imran","family":"Ullah","sequence":"first","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan C.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daouda","family":"Ndiaye","sequence":"additional","affiliation":[{"name":"International Research & Training Center in Applied Genomics and Health Surveillance (CIGASS), Cheikh Anta Diop University, Dakar, Senegal"},{"name":"Department of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K.","family":"Volkman","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dyann F.","family":"Wirth","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100309201063000_2026.09.03.749253v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12876"},{"key":"2026100309201063000_2026.09.03.749253v2.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260867"},{"key":"2026100309201063000_2026.09.03.749253v2.3","unstructured":"Compendium of molecular markers for antimalarial drug resistance. https:\/\/www.who.int\/publications\/m\/item\/compendium-of-molecular-markers-for-antimalarial-drug-resistance (2025)."},{"key":"2026100309201063000_2026.09.03.749253v2.4","unstructured":"Organization WH. WHO Guidelines for malaria. 2023:447. WHO\/UCN\/GMP\/2023.01 https:\/\/www.who.int\/publications\/i\/item\/guidelines-for-malaria. (2023)."},{"key":"2026100309201063000_2026.09.03.749253v2.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax4735"},{"key":"2026100309201063000_2026.09.03.749253v2.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1104063108"},{"key":"2026100309201063000_2026.09.03.749253v2.7","doi-asserted-by":"crossref","unstructured":"Stokes, B. H. et al. Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness. Elife 10, (2021).","DOI":"10.7554\/eLife.66277"},{"key":"2026100309201063000_2026.09.03.749253v2.8","doi-asserted-by":"crossref","first-page":"e1009266","DOI":"10.1371\/journal.pgen.1009266","article-title":"Genetic background and PfKelch13 affect artemisinin susceptibility of PfCoronin mutants in Plasmodium falciparum","volume":"16","year":"2020","journal-title":"PLoS Genet"},{"key":"2026100309201063000_2026.09.03.749253v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3189"},{"key":"2026100309201063000_2026.09.03.749253v2.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2101746"},{"key":"2026100309201063000_2026.09.03.749253v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1005-2"},{"key":"2026100309201063000_2026.09.03.749253v2.12","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-13-472"},{"key":"2026100309201063000_2026.09.03.749253v2.13","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-020-03193-w"},{"key":"2026100309201063000_2026.09.03.749253v2.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpddr.2021.07.004"},{"key":"2026100309201063000_2026.09.03.749253v2.15","doi-asserted-by":"publisher","DOI":"10.1101\/2025.11.05.686777"},{"key":"2026100309201063000_2026.09.03.749253v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2925"},{"key":"2026100309201063000_2026.09.03.749253v2.17","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(13)70252-4"},{"key":"2026100309201063000_2026.09.03.749253v2.18","doi-asserted-by":"crossref","first-page":"102177","DOI":"10.1016\/j.redox.2021.102177","article-title":"Protein abundance and folding rather than the redox state of Kelch13 determine the artemisinin susceptibility of Plasmodium falciparum","volume":"48","year":"2021","journal-title":"Redox Biol"},{"key":"2026100309201063000_2026.09.03.749253v2.19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1612765"},{"key":"2026100309201063000_2026.09.03.749253v2.20","doi-asserted-by":"crossref","unstructured":"Stokes, B. H. et al. Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness. Elife 10, (2021).","DOI":"10.7554\/eLife.66277"},{"key":"2026100309201063000_2026.09.03.749253v2.21","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1038\/s41467-026-72834-6","article-title":"Cellular and molecular basis of PfCoronin function in artemisinin resistance in Plasmodium falciparum","volume":"17","year":"2026","journal-title":"Nat. Commun"},{"key":"2026100309201063000_2026.09.03.749253v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20805-w"},{"key":"2026100309201063000_2026.09.03.749253v2.23","doi-asserted-by":"crossref","unstructured":"Simwela, N. V. et al. Plasmodium berghei K13 Mutations Mediate In Vivo Artemisinin Resistance That Is Reversed by Proteasome Inhibition. MBio 11, (2020).","DOI":"10.1128\/mBio.02312-20"},{"key":"2026100309201063000_2026.09.03.749253v2.24","doi-asserted-by":"crossref","unstructured":"Straimer, J. et al. Plasmodium falciparum K13 Mutations Differentially Impact Ozonide Susceptibility and Parasite Fitness In Vitro. MBio 8, (2017).","DOI":"10.1128\/mBio.00172-17"},{"key":"2026100309201063000_2026.09.03.749253v2.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36921-2"},{"key":"2026100309201063000_2026.09.03.749253v2.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1812317115"},{"key":"2026100309201063000_2026.09.03.749253v2.27","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.5.1803-1806.2004"},{"key":"2026100309201063000_2026.09.03.749253v2.28","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkw449"},{"key":"2026100309201063000_2026.09.03.749253v2.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-04407-z"},{"key":"2026100309201063000_2026.09.03.749253v2.30","unstructured":"Ullah, I. et al. The relative rate of kill of the MMV Malaria Box compounds provides links to the mode of antimalarial action and highlights scaffolds of medicinal chemistry interest. J. Antimicrob. Chemother."}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.03.749253","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:20:19Z","timestamp":1791044419000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.03.749253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":30,"URL":"https:\/\/doi.org\/10.64898\/2026.09.03.749253","relation":{},"subject":[],"published":{"date-parts":[[2026,9,7]]},"subtype":"preprint"}}