{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:54:00Z","timestamp":1789908840744,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011118","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000}}],"reference-count":97,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T00:00:00Z","timestamp":1674604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001459","name":"Singapore Ministry of Education","doi-asserted-by":"crossref","award":["MOE2019-T3-1-007"],"award-info":[{"award-number":["MOE2019-T3-1-007"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001349","name":"Singapore National Medical Research Council","doi-asserted-by":"crossref","award":["OFIRG21nov-0014"],"award-info":[{"award-number":["OFIRG21nov-0014"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Resistance of the human malaria parasites, <jats:italic>Plasmodium falciparum<\/jats:italic>, to artemisinins is now fully established in Southeast Asia and is gradually emerging in Sub-Saharan Africa. Although nonsynonymous SNPs in the <jats:italic>pfk13<\/jats:italic> Kelch-repeat propeller (KREP) domain are clearly associated with artemisinin resistance, their functional relevance requires cooperation with other genetic factors\/alterations of the <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic> genome, collectively referred to as genetic background. Here we provide experimental evidence that <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic> cyclophilin 19B (PfCYP19B) may represent one putative factor in this genetic background, contributing to artemisinin resistance via its increased expression. We show that overexpression of PfCYP19B <jats:italic>in vitro<\/jats:italic> drives limited but significant resistance to not only artemisinin but also piperaquine, an important partner drug in artemisinin-based combination therapies. We showed that PfCYP19B acts as a negative regulator of the integrated stress response (ISR) pathway by modulating levels of phosphorylated eIF2\u03b1 (eIF2\u03b1-P). Curiously, artemisinin and piperaquine affect eIF2\u03b1-P in an inverse direction that in both cases can be modulated by PfCYP19B towards resistance. Here we also provide evidence that the upregulation of PfCYP19B in the drug-resistant parasites appears to be maintained by a short tandem repeat (SRT) sequence polymorphism in the gene\u2019s promoter region. These results support a model that artemisinin (and other drugs) resistance mechanisms are complex genetic traits being contributed to by altered expression of multiple genes driven by genetic polymorphism at their promoter regions.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011118","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T18:40:03Z","timestamp":1674672003000},"page":"e1011118","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Short tandem repeat polymorphism in the promoter region of cyclophilin 19B drives its transcriptional upregulation and contributes to drug resistance in the malaria parasite Plasmodium falciparum"],"prefix":"10.1371","volume":"19","author":[{"given":"Michal","family":"Kucharski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grennady","family":"Wirjanata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sourav","family":"Nayak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine","family":"Boentoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerzy Michal","family":"Dziekan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Assisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob W.","family":"van der 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