{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:14:18Z","timestamp":1791490458609,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009659","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000}}],"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100007469","name":"Alfred Benzon Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007469","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AI125988"],"award-info":[{"award-number":["R21AI125988"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR002553"],"award-info":[{"award-number":["UL1TR002553"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Sickle-trait hemoglobin protects against severe <jats:italic>Plasmodium falciparum<\/jats:italic> malaria. Severe malaria is governed in part by the expression of the <jats:italic>Plasmodium falciparum<\/jats:italic> Erythrocyte Membrane Protein 1 (PfEMP1) that are encoded by <jats:italic>var<\/jats:italic> genes, specifically those variants that bind Endothelial Protein C Receptor (EPCR). In this study, we investigate the effect of sickle-trait on parasite <jats:italic>var<\/jats:italic> gene expression and function <jats:italic>in vitro<\/jats:italic> and in field-collected parasites. We mapped <jats:italic>var<\/jats:italic> gene reads generated from RNA sequencing in parasite cultures in normal and sickle-cell trait blood throughout the asexual lifecycle. We investigated sickle-trait effect on PfEMP1 interactions with host receptors CD36 and EPCR using static adhesion assays and flow cytometry. <jats:italic>Var<\/jats:italic> expression <jats:italic>in vivo<\/jats:italic> was compared by assembling <jats:italic>var<\/jats:italic> domains sequenced from total RNA in parasites infecting Malian children with HbAA and HbAS. Sickle-trait did not alter the abundance or type of <jats:italic>var<\/jats:italic> gene transcripts <jats:italic>in vitro<\/jats:italic>, nor the abundance of overall transcripts or of <jats:italic>var<\/jats:italic> functional domains <jats:italic>in vivo<\/jats:italic>. In adhesion assays using recombinant host receptors, sickle-trait reduced adhesion by 73\u201386% to CD36 and 83% to EPCR. Similarly, sickle-trait reduced the surface expression of EPCR-binding PfEMP1. In conclusion, Sickle-cell trait does not directly affect <jats:italic>var<\/jats:italic> gene transcription but does reduce the surface expression and function of PfEMP1. This provides a direct mechanism for protection against severe malaria conferred by sickle-trait hemoglobin.<\/jats:p>\n<jats:p><jats:bold>Trial Registration:<\/jats:bold> ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02645604\" xlink:type=\"simple\">NCT02645604<\/jats:ext-link>.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009659","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T17:41:29Z","timestamp":1623433289000},"page":"e1009659","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Sickle-trait hemoglobin reduces adhesion to both CD36 and EPCR by Plasmodium falciparum-infected erythrocytes"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5567-465X","authenticated-orcid":true,"given":"Jens E. 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M.","family":"Fairhurst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahamadou","family":"Diakit\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2783-0990","authenticated-orcid":true,"given":"Steve M.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"key":"ppat.1009659.ref001","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S1473-3099(12)70055-5","article-title":"Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis","volume":"12","author":"SM Taylor","year":"2012","journal-title":"Lancet Infect Dis"},{"key":"ppat.1009659.ref002","doi-asserted-by":"crossref","first-page":"7350","DOI":"10.1073\/pnas.1804388115","article-title":"Resistance 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