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Partial resistance of\n              <jats:italic>P. falciparum<\/jats:italic>\n              to artemisinin has been associated with mutations in the propeller domain of the\n              <jats:italic>Pfkelch13<\/jats:italic>\n              gene, resulting in a fraction of ring stages that are able to survive exposure to artemisinin through a temporary growth arrest. Here, we investigated whether the growth arrest in ring-stage parasites reflects a general response to stress. We mimicked a stressful environment\n              <jats:italic>in vitro<\/jats:italic>\n              by exposing parasites to chloroquine or dihydroartemisinin (DHA). We observed that early ring-stage parasites pre-exposed to a stressed culture supernatant exhibited a temporary growth arrest and a reduced susceptibility to DHA, as assessed by the ring-stage survival assay, irrespective of their\n              <jats:italic>Pfkelch13<\/jats:italic>\n              genotype. These data suggest that temporary growth arrest of early ring stages may be a constitutive,\n              <jats:italic>Pfkelch13<\/jats:italic>\n              -independent survival mechanism in\n              <jats:italic>P. falciparum<\/jats:italic>\n              .\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                <jats:italic>Plasmodium falciparum<\/jats:italic>\n                ring stages have the ability to sense the extracellular environment, regulate their growth, and enter a temporary growth arrest state in response to adverse conditions such as drug exposure. This temporary growth arrest results in reduced susceptibility to artemisinin\n                <jats:italic>in vitro<\/jats:italic>\n                . The signal responsible for this process is thought to be small molecules (less than 3 kDa) released by stressed mature-stage parasites. These data suggest that Pfkelch13-dependent artemisinin resistance and the growth arrest phenotype are two complementary but unrelated mechanisms of ring-stage survival in\n                <jats:italic>P. falciparum<\/jats:italic>\n                . This finding provides new insights into the field of\n                <jats:italic>P. falciparum<\/jats:italic>\n                antimalarial drug resistance by highlighting the extracellular compartment and cellular communication as an understudied mechanism.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03500-23","type":"journal-article","created":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T14:00:31Z","timestamp":1708092031000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Drug-induced stress mediates\n            <i>Plasmodium falciparum<\/i>\n            ring-stage growth arrest and reduces\n            <i>in vitro<\/i>\n            parasite susceptibility to artemisinin"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7894-5977","authenticated-orcid":false,"given":"Lucien","family":"Platon","sequence":"first","affiliation":[{"name":"Malaria Genetics and Resistance Unit, INSERM U1201, Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"Sorbonne Universit\u00e9, Coll\u00e8ge Doctoral ED 515 Complexit\u00e9 du Vivant, Paris, France"},{"name":"Malaria Parasite Biology and Vaccines Unit, Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"Institute of Parasitology and Tropical Diseases, UR7292 Dynamics of Host\u2013Pathogen Interactions, Universit\u00e9 de Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Leroy","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, Medicines for Malaria Venture, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6753-8938","authenticated-orcid":false,"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, USA"},{"name":"Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1357-4495","authenticated-orcid":false,"given":"Didier","family":"M\u00e9nard","sequence":"additional","affiliation":[{"name":"Malaria Genetics and Resistance Unit, INSERM U1201, Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"Malaria Parasite Biology and Vaccines Unit, Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"Institute of Parasitology and Tropical Diseases, UR7292 Dynamics of Host\u2013Pathogen Interactions, Universit\u00e9 de Strasbourg, Strasbourg, France"},{"name":"Laboratory of Parasitology and Medical Mycology, CHU Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2007.77.181"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1999.0426"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(94)90471-5"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12876"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1314981"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2101746"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808859"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(19)30392-5"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30228-0"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01121-21"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51015"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1513137"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009133"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2117480"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260867"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)70032-0"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1005-2"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2210956"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2211803"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02641-9"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(13)70252-4"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1104063108"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10111"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.095"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax4735"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20805-w"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1006\/expr.1995.1149"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01636-09"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1209823109"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.169.1.357"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.18-0894"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1086\/656476"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","unstructured":"Tripathi 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