{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:53:36Z","timestamp":1780448016882,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009839","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T00:00:00Z","timestamp":1630972800000}}],"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1R01AI153599-01"],"award-info":[{"award-number":["1R01AI153599-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"national institute of allergy and infectious diseases","doi-asserted-by":"publisher","award":["1R01AI153599-01"],"award-info":[{"award-number":["1R01AI153599-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"national institute of allergy and infectious diseases","doi-asserted-by":"publisher","award":["1R15AI144683-01"],"award-info":[{"award-number":["1R15AI144683-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007135","name":"university of tennessee","doi-asserted-by":"publisher","award":["STIR SEED Grant"],"award-info":[{"award-number":["STIR SEED Grant"]}],"id":[{"id":"10.13039\/100007135","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Masking the immunogenic cell wall epitope \u00df(1,3)-glucan under an outer layer of mannosylated glycoproteins is an important virulence factor deployed by <jats:italic>Candida albicans<\/jats:italic> during infection. Consequently, increased \u00df(1,3)-glucan exposure (unmasking) reveals <jats:italic>C<\/jats:italic>. <jats:italic>albicans<\/jats:italic> to the host\u2019s immune system and attenuates its virulence. We have previously shown that activation of the Cek1 MAPK pathway via expression of a hyperactive allele of an upstream kinase (<jats:italic>STE11<\/jats:italic><jats:sup><jats:italic>\u0394N467<\/jats:italic><\/jats:sup>) induced unmasking. It also increased survival of mice in a murine disseminated candidiasis model and attenuated kidney fungal burden by \u226533 fold. In this communication, we utilized cyclophosphamide-induced immunosuppression to test if the clearance of the unmasked <jats:italic>STE11<\/jats:italic><jats:sup><jats:italic>\u0394N467<\/jats:italic><\/jats:sup> mutant was dependent on the host immune system. Suppression of the immune response by cyclophosphamide reduced the attenuation in fungal burden caused by the <jats:italic>STE11<\/jats:italic><jats:sup><jats:italic>\u0394N467<\/jats:italic><\/jats:sup> allele. Moreover, specific depletion of neutrophils via 1A8 antibody treatment also reduced <jats:italic>STE11<\/jats:italic><jats:sup><jats:italic>\u0394N467<\/jats:italic><\/jats:sup>-dependent fungal burden attenuation, but to a lesser extent than cyclophosphamide, demonstrating an important role for neutrophils in mediating fungal clearance of unmasked <jats:italic>STE11<\/jats:italic><jats:sup><jats:italic>\u0394N467<\/jats:italic><\/jats:sup> cells. In an effort to understand the mechanism by which Ste11<jats:sup>\u0394N467<\/jats:sup> causes unmasking, transcriptomics were used to reveal that several components in the Cek1 MAPK pathway were upregulated, including the transcription factor <jats:italic>CPH1<\/jats:italic> and the cell wall sensor <jats:italic>DFI1<\/jats:italic>. In this report we show that a <jats:italic>cph1\u0394\u0394<\/jats:italic> mutation restored \u00df(1,3)-glucan exposure to wild-type levels in the <jats:italic>STE11<\/jats:italic><jats:sup><jats:italic>\u0394N467<\/jats:italic><\/jats:sup> strain, confirming that Cph1 is the transcription factor mediating Ste11<jats:sup>\u0394N467<\/jats:sup>-induced unmasking. Furthermore, Cph1 is shown to induce a positive feedback loop that increases Cek1 activation. In addition, full unmasking by <jats:italic>STE11<\/jats:italic><jats:sup><jats:italic>\u0394N467<\/jats:italic><\/jats:sup> is dependent on the upstream cell wall sensor <jats:italic>DFI1<\/jats:italic>. However, while deletion of <jats:italic>DFI1<\/jats:italic> significantly reduced Ste11<jats:sup>\u0394N467<\/jats:sup>-induced unmasking, it did not impact activation of the downstream kinase Cek1. Thus, it appears that once stimulated by Ste11<jats:sup>\u0394N467<\/jats:sup>, Dfi1 activates a parallel signaling pathway that is involved in Ste11<jats:sup>\u0394N467<\/jats:sup>-induced unmasking.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009839","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T17:40:42Z","timestamp":1629913242000},"page":"e1009839","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Activation of Cph1 causes \u00df(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6777-4006","authenticated-orcid":true,"given":"Andrew S.","family":"Wagner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3353-6042","authenticated-orcid":true,"given":"Trevor J.","family":"Hancock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen W.","family":"Lumsdaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8537-9085","authenticated-orcid":true,"given":"Sarah J.","family":"Kauffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4576-072X","authenticated-orcid":true,"given":"Mikayla M.","family":"Mangrum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3361-7475","authenticated-orcid":true,"given":"Elise K.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5543-6691","authenticated-orcid":true,"given":"Timothy E.","family":"Sparer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2867-7182","authenticated-orcid":true,"given":"Todd B.","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"issue":"165","key":"ppat.1009839.ref001","doi-asserted-by":"crossref","first-page":"165rv13","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: human fungal infections","volume":"4","author":"GD Brown","year":"2012","journal-title":"Sci Transl Med."},{"issue":"10","key":"ppat.1009839.ref002","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/nri3897","article-title":"Immune defence against Candida fungal infections","volume":"15","author":"MG Netea","year":"2015","journal-title":"Nat Rev Immunol"},{"issue":"3","key":"ppat.1009839.ref003","article-title":"The Fungal Cell Wall: Structure, Biosynthesis, and Function","volume":"5","author":"NAR Gow","year":"2017","journal-title":"Microbiol Spectr."},{"issue":"4","key":"ppat.1009839.ref004","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.tim.2018.01.007","article-title":"Dynamic Fungal Cell Wall Architecture in Stress Adaptation and Immune Evasion","volume":"26","author":"A Hopke","year":"2018","journal-title":"Trends Microbiol"},{"issue":"12","key":"ppat.1009839.ref005","doi-asserted-by":"crossref","first-page":"e1000227","DOI":"10.1371\/journal.ppat.1000227","article-title":"Dynamic, morphotype-specific Candida albicans beta-glucan exposure during infection and drug treatment","volume":"4","author":"RT Wheeler","year":"2008","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1009839.ref006","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1371\/journal.ppat.0020035","article-title":"A drug-sensitive genetic network masks fungi from the immune system","volume":"2","author":"RT Wheeler","year":"2006","journal-title":"PLoS Pathog"},{"issue":"10","key":"ppat.1009839.ref007","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1086\/523110","article-title":"Immune recognition of Candida albicans beta-glucan by dectin-1","volume":"196","author":"NA Gow","year":"2007","journal-title":"J Infect Dis"},{"issue":"3","key":"ppat.1009839.ref008","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1084\/jem.20020470","article-title":"Dectin-1 is a major beta-glucan receptor on macrophages","volume":"196","author":"GD Brown","year":"2002","journal-title":"J Exp Med"},{"issue":"6851","key":"ppat.1009839.ref009","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/35092620","article-title":"Immune recognition. 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