{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:35:54Z","timestamp":1793140554240,"version":"4.5.0"},"reference-count":66,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Institut Pasteur","award":["Pasteur-Roux-Cantarini Fellowship"],"award-info":[{"award-number":["Pasteur-Roux-Cantarini Fellowship"]}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"crossref","award":["E-26\/204.456\/2021"],"award-info":[{"award-number":["E-26\/204.456\/2021"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"crossref","award":["39712ZK"],"award-info":[{"award-number":["39712ZK"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ResistEV AAPG2021 CE35"],"award-info":[{"award-number":["ResistEV AAPG2021 CE35"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Institut Pasteur","award":["Pasteur - Paris University (PPU) International PhD Program"],"award-info":[{"award-number":["Pasteur - Paris University (PPU) International PhD Program"]}]},{"DOI":"10.13039\/100007631","name":"Canadian Institute for Advanced Research","doi-asserted-by":"crossref","award":["CIFAR Azrieli Global Scholar Award"],"award-info":[{"award-number":["CIFAR Azrieli Global Scholar Award"]}],"id":[{"id":"10.13039\/100007631","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Resistance to fluconazole (FLC), the most widely used antifungal drug, is typically achieved by altering the azole drug target and\/or drug efflux pumps. Recent reports have suggested a link between vesicular trafficking and antifungal resistance. Here, we identified novel\n            <jats:italic>Cryptococcus neoformans<\/jats:italic>\n            regulators of extracellular vesicle (EV) biogenesis that impact FLC resistance. In particular, the transcription factor Hap2 does not affect the expression of the drug target or efflux pumps, yet it impacts the cellular sterol profile. Subinhibitory FLC concentrations also downregulate EV production. Moreover,\n            <jats:italic>in vitro<\/jats:italic>\n            spontaneous FLC-resistant colonies showed altered EV production, and the acquisition of FLC resistance was associated with decreased EV production in clinical isolates. Finally, the reversion of FLC resistance was associated with increased EV production. These data suggest a model in which fungal cells can regulate EV production in place of regulating the drug target gene expression as a first line of defense against antifungal assault in this fungal pathogen.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Extracellular vesicles (EVs) are membrane-enveloped particles that are released by cells into the extracellular space. Fungal EVs can mediate community interactions and biofilm formation, but their functions remain poorly understood. Here, we report the identification of the first regulators of EV production in the major fungal pathogen\n              <jats:italic>Cryptococcus neoformans<\/jats:italic>\n              . Surprisingly, we uncover a novel role of EVs in modulating antifungal drug resistance. Disruption of EV production was associated with altered lipid composition and changes in fluconazole susceptibility. Spontaneous azole-resistant mutants were deficient in EV production, while loss of resistance restored initial EV production levels. These findings were recapitulated in\n              <jats:italic>C. neoformans<\/jats:italic>\n              clinical isolates, indicating that azole resistance and EV production are coregulated in diverse strains. Our study reveals a new mechanism of drug resistance in which cells adapt to azole stress by modulating EV production.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.00870-23","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T15:29:27Z","timestamp":1686670167000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":27,"title":["Coregulation of extracellular vesicle production and fluconazole susceptibility in\n            <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1128","author":[{"given":"Juliana","family":"Rizzo","sequence":"first","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Unit\u00e9 Biologie des ARN des Pathog\u00e8nes Fongiques , Paris, France"},{"name":"Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ad\u00e8le","family":"Trottier","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Unit\u00e9 Biologie des ARN des Pathog\u00e8nes Fongiques , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9rique","family":"Moyrand","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Unit\u00e9 Biologie des ARN des Pathog\u00e8nes Fongiques , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Yves","family":"Copp\u00e9e","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Unit\u00e9 Biologie des ARN des Pathog\u00e8nes Fongiques , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Maufrais","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Unit\u00e9 Biologie des ARN des Pathog\u00e8nes Fongiques , Paris, France"},{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, USR 3756 IP CNRS, HUB Bioinformatique et Biostatistique , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Claudia G.","family":"Zimbres","sequence":"additional","affiliation":[{"name":"Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi Tuong Vi","family":"Dang","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Unit\u00e9 Biologie des ARN des Pathog\u00e8nes Fongiques , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9726-3082","authenticated-orcid":true,"given":"Alexandre","family":"Alanio","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Centre National de R\u00e9f\u00e9rence Mycoses Invasives et Antifongiques, Groupe de recherche Mycologie Translationnelle, D\u00e9partement de Mycologie , Paris, France"},{"name":"Laboratoire de parasitologie-mycologie, AP-HP, H\u00f4pital Saint-Louis , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Desnos-Ollivier","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Centre National de R\u00e9f\u00e9rence Mycoses Invasives et Antifongiques, Groupe de recherche Mycologie Translationnelle, D\u00e9partement de Mycologie , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Mouyna","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Unit\u00e9 Biologie des ARN des Pathog\u00e8nes Fongiques , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e9rard","family":"P\u00e9hau-Arnaude","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Plateforme de Bio-Imagerie Ultrastructurale , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Henri","family":"Commere","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Cytometry and Biomarkers , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Novault","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Cytometry and Biomarkers , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0390-7084","authenticated-orcid":true,"given":"Iuliana V.","family":"Ene","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Fungal Heterogeneity Group , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Nimrichter","sequence":"additional","affiliation":[{"name":"Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcio L.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil"},{"name":"Instituto Carlos Chagas, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ) , Curitiba, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4788-1154","authenticated-orcid":true,"given":"Guilhem","family":"Janbon","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Unit\u00e9 Biologie des ARN des Pathog\u00e8nes Fongiques , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2023,6,13]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00449-20"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41435-019-0071-2"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004404"},{"key":"e_1_3_6_5_2","unstructured":"Anonymous\n. 2022. Who fungal priority pathogens list to guide research development and public health action. Available from: https:\/\/www.who.int\/publications-detail-redirect\/9789240060241"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30243-8"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00720-1"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00214"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-030117-020345"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0322-2"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.11.3653-3656.2003"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000848"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124516"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00346"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12129"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/femsml\/uqab009"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01347-18"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e06-02-0125"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01998-18"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI145123"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1242\/bio.011528"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.54160"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2006872"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2022.2098058"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26525-z"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-019-0538-8"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111121"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7757"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-42778-7"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/femsyr\/foaa015"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.01645"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.176.18.5802-5813.1994"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32249-5"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes11070795"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00953"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.8.1856"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05502-11"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.13217"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00080-19"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/mr.57.2.383-401.1993"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2010.0069"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/cfg.254"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2016.10.011"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.233569"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201489468"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001209"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2012.08.006"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00080-15"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31308-1"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00273-13"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.3389\/ffunb.2022.957577"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2001.02651.x"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004261"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.9.4831-4841.2003"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05695.x"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2020.103364"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122916"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2019.1697028"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00189-08"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa060"},{"key":"e_1_3_6_61_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-3-r25"},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-4-r36"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_6_64_2","doi-asserted-by":"crossref","unstructured":"Maufrais C de Oliveira L Bastos RW Moyrand F Reis FCG Valero C Gimenez B Josefowicz LJ Goldman GH Rodrigues ML Janbon G\n. 2021. Population genomic analysis of Cryptococcus Brazilian isolates reveals an African type subclade distribution. G3 (Bethesda) 11:jkab107. doi:10.1093\/g3journal\/jkab107 jkab107","DOI":"10.1093\/g3journal\/jkab107"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty191"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04926-x"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00870-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00870-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T15:29:35Z","timestamp":1686670175000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.00870-23"}},"subtitle":[],"editor":[{"given":"Yong-Sun","family":"Bahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,6,13]]},"references-count":66,"alternative-id":["10.1128\/mbio.00870-23"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00870-23","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,13]]},"assertion":[{"value":"2023-04-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00870-23"}}