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In previous studies, virulence gene expression was analyzed in samples from volunteers infected with the\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    (Pf) NF54 isolate, which is of African origin. Here, we provide an in-depth investigation of parasite virulence gene expression in malaria-na\u00efve European volunteers undergoing CHMI with the genetically distinct Pf 7G8 clone, originating in Brazil. Differential expression of\n                    <jats:italic>var<\/jats:italic>\n                    genes, encoding major virulence factors of Pf, PfEMP1s, was assessed in\n                    <jats:italic>ex vivo<\/jats:italic>\n                    parasite samples as well as in parasites from the\n                    <jats:italic>in vitro<\/jats:italic>\n                    cell bank culture that was used to generate the sporozoites (SPZ) for CHMI (Sanaria PfSPZ Challenge (7G8)). We report broad activation of mainly B-type subtelomeric located\n                    <jats:italic>var<\/jats:italic>\n                    genes at the onset of a 7G8 blood stage infection in na\u00efve volunteers, mirroring the NF54 expression study and suggesting that the expression of virulence-associated genes is generally reset during transmission from the mosquito to the human host. However, in 7G8 parasites, we additionally detected a continuously expressed single C-type variant, Pf7G8_040025600, that was most highly expressed in both pre-mosquito cell bank and volunteer samples, suggesting that 7G8, unlike NF54, maintains expression of some previously expressed\n                    <jats:italic>var<\/jats:italic>\n                    variants during transmission. This suggests that in a new host, the parasite may preferentially express the variants that previously allowed successful infection and transmission.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial registration:<\/jats:bold>\n                    ClinicalTrials.gov -\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02704533\" xlink:type=\"simple\">NCT02704533<\/jats:ext-link>\n                    ; 2018-004523-36\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011468","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T14:22:20Z","timestamp":1688048540000},"page":"e1011468","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["The exception that proves the rule: Virulence gene expression at the onset of Plasmodium falciparum blood stage infections"],"prefix":"10.1371","volume":"19","author":[{"given":"Jan Stephan","family":"Wichers-Misterek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Krumkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Held","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidrun","family":"von Thien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Wittmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick Daniel","family":"H\u00f6ppner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia M.","family":"Ruge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Moser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Dara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Strauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meral","family":"Esen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Fendel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zita","family":"Sulyok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam D.","family":"Jeninga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G.","family":"Kremsner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. Kim Lee","family":"Sim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Duffy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D.","family":"Otto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim-Wolf","family":"Gilberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana C.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Mordm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Petter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8397-7308","authenticated-orcid":true,"given":"Anna","family":"Bachmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,6,29]]},"reference":[{"issue":"6872","key":"ppat.1011468.ref001","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/415673a","article-title":"The pathogenic basis of malaria","volume":"415","author":"LH Miller","year":"2002","journal-title":"Nature"},{"issue":"6906","key":"ppat.1011468.ref002","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature01097","article-title":"Genome sequence of the human malaria parasite Plasmodium falciparum","volume":"419","author":"MJ Gardner","year":"2002","journal-title":"Nature"},{"issue":"5","key":"ppat.1011468.ref003","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1046\/j.1365-2958.2003.03814.x","article-title":"Evidence for the importance of genetic structuring to the structural and functional specialization of the Plasmodium falciparum var gene family","volume":"50","author":"SM Kraemer","year":"2003","journal-title":"Mol Microbiol"},{"key":"ppat.1011468.ref004","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/1475-2875-2-27","article-title":"Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions.","volume":"2","author":"T Lavstsen","year":"2003","journal-title":"Malar J."},{"issue":"9","key":"ppat.1011468.ref005","article-title":"Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes\u2014divide and conquer.","volume":"6","author":"TS Rask","year":"2010","journal-title":"PLoS Comput Biol."},{"issue":"9","key":"ppat.1011468.ref006","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1084\/jem.20040274","article-title":"Plasmodium falciparum associated with severe childhood malaria preferentially expresses PfEMP1 encoded by group A var genes","volume":"199","author":"AT Jensen","year":"2004","journal-title":"J Exp Med"},{"issue":"3","key":"ppat.1011468.ref007","doi-asserted-by":"crossref","first-page":"e26","DOI":"10.1371\/journal.ppat.0010026","article-title":"Plasmodium falciparum variant surface antigen expression patterns during malaria.","volume":"1","author":"PC Bull","year":"2005","journal-title":"PLoS Pathog."},{"issue":"51","key":"ppat.1011468.ref008","doi-asserted-by":"crossref","first-page":"21801","DOI":"10.1073\/pnas.0907590106","article-title":"Plasmodium falciparum var gene expression is modified by host immunity","volume":"106","author":"GM Warimwe","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"26","key":"ppat.1011468.ref009","doi-asserted-by":"crossref","first-page":"E1791","DOI":"10.1073\/pnas.1120455109","article-title":"Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children","volume":"109","author":"T Lavstsen","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"ppat.1011468.ref010","doi-asserted-by":"crossref","first-page":"839","DOI":"10.15252\/emmm.201606188","article-title":"Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRalpha1 domains","volume":"8","author":"JS Jespersen","year":"2016","journal-title":"EMBO Mol Med"},{"issue":"5","key":"ppat.1011468.ref011","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.chom.2017.09.009","article-title":"Linking EPCR-Binding PfEMP1 to","volume":"22","author":"A Kessler","year":"2017","journal-title":"Brain Swelling in Pediatric Cerebral Malaria. 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