{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T20:45:57Z","timestamp":1787863557702,"version":"build-2784847793"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","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","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","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Cryptococcus neoformans<\/jats:italic> is a fungal pathogen causing life-threatening meningoencephalitis in susceptible individuals. Fungal vaccine development has been hampered by the fact that cryptococcosis occurs during immunodeficiency. We previously reported that a <jats:italic>C. neoformans<\/jats:italic> mutant (\u0394<jats:italic>sgl1<\/jats:italic>) accumulating sterylglucosides (SGs) is avirulent and provides complete protection to WT challenge, even under CD4<jats:sup>+<\/jats:sup> T cell depletion, an immunodeficient condition commonly associated with cryptococcosis. We found high levels of SGs in the lungs post-immunization with \u0394<jats:italic>sgl1<\/jats:italic> that decreased upon fungal clearance. Th1 cytokines increased whereas Th2 cytokines concurrently decreased, coinciding with a large recruitment of leukocytes to the lungs. Depletion of B or CD8<jats:sup>+<\/jats:sup> T cells did not affect either \u0394<jats:italic>sgl1<\/jats:italic> clearance or protection from WT challenge. Although CD4<jats:sup>+<\/jats:sup> T cell depletion affected clearance, mice were still protected indicating that clearance of the mutant was not necessary for host protection. Protection was lost only when both CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells were depleted, highlighting a previously unexplored role of fungal-derived SGs as an immunoadjuvant for host protection against cryptococcosis.<\/jats:p>","DOI":"10.3389\/fcimb.2021.739027","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T05:04:27Z","timestamp":1631077467000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":34,"title":["Cryptococcus neoformans \u0394sgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection"],"prefix":"10.3389","volume":"11","author":[{"given":"Tyler G.","family":"Normile","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Rella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Del Poeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1093\/qjmed\/hcz299","article-title":"Cryptococcus and HIV","volume":"113","author":"Akhtar","year":"2020","journal-title":"QJM"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7224","DOI":"10.1128\/AAC.01698-15","article-title":"Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients With HIV-Associated Cryptococcal Meningitis","volume":"59","author":"Bicanic","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"B3","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1139\/o59-099","article-title":"A Rapid Method of Total Lipid Extraction and Purification","volume":"37","author":"Bligh","year":"1959","journal-title":"Can. J. Biochem. Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/s0192-0561(97)85551-8","article-title":"Beta-Sitosterol and Beta-Sitosterolglucoside Stimulate Human Peripheral Blood Lymphocyte Proliferation: Implications for Their Use as an Immunomodulatory Vitamin Combination","volume":"18","author":"Bouic","year":"1996","journal-title":"Int. J. Immunopharmac"},{"key":"B5","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.jinf.2018.06.016","article-title":"Reactivation of Dormant\/Latent Fungal Infection","volume":"77","author":"Brunet","year":"2018","journal-title":"J. Infect."},{"key":"B6","doi-asserted-by":"publisher","first-page":"4546","DOI":"10.1172\/JCI136068","article-title":"FTY720 Reactivates Cryptococcal Granulomas in Mice Through S1P Receptor 3 on Macrophages","volume":"130","author":"Bryan","year":"2020","journal-title":"J. Clin. Invest."},{"key":"B7","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.tim.2017.10.002","article-title":"A Call to Arms: Quest for a Cryptococcal Vaccine","volume":"26","author":"Caballero Van Dyke","year":"2018","journal-title":"Trends Microbiol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fpls.2019.01162","article-title":"Inactivation of UDP-Glucose Sterol Glucosyltransferases Enhances Arabidopsis Resistance to Botrytis Cinerea","volume":"10","author":"Castillo","year":"2019","journal-title":"Front. Plant Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jof2010001","article-title":"Colliding Epidemics and the Rise of Cryptococcosis","volume":"2","author":"Chang","year":"2015","journal-title":"J. Fungi (Basel)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41577-020-0274-9","article-title":"CD8(+) T Cells in HIV Control, Cure and Prevention","volume":"20","author":"Collins","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"B11","article-title":"Structure and Inhibition of Cryptococcus Neoformans Sterylglucosidase to Develop Antifungal Agents","author":"de Sa","year":"2021","journal-title":"Nat. Commun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.wem.2019.10.004","article-title":"The Disease Ecology, Epidemiology, Clinical Manifestations, and Management of Emerging Cryptococcus Gattii Complex Infections","volume":"31","author":"Diaz","year":"2020","journal-title":"Wilderness Environ. Med."},{"key":"B13","first-page":"518","article-title":"A Randomised Placebo-Controlled Trial of the Efficacy of Beta-Sitosterol and its Glucoside as Adjuvants in the Treatment of Pulmonary Tuberculosis","volume":"1","author":"Donald","year":"1994","journal-title":"Int. J. Tuberc Lung Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1080\/21505594.2019.1664719","article-title":"Invasive Endemic Fungi of the Western Hemisphere","volume":"10","author":"Fierer","year":"2019","journal-title":"Virulence"},{"key":"B15","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.msard.2016.07.015","article-title":"Immunologic Mechanisms of Fingolimod and the Role of Immunosenescence in the Risk of Cryptococcal Infection: A Case Report and Review of Literature","volume":"9","author":"Grebenciucova","year":"2016","journal-title":"Mult Scler Relat. Disord."},{"key":"B16","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.plipres.2010.02.001","article-title":"The Functions of Steryl Glycosides Come to Those Who Wait: Recent Advances in Plants, Fungi, Bacteria and Animals","volume":"49","author":"Grille","year":"2010","journal-title":"Prog. Lipid Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1016\/j.vaccine.2019.10.051","article-title":"Protection of Mice Against Experimental Cryptococcosis Using Glucan Particle-Based Vaccines Containing Novel Recombinant Antigens","volume":"38","author":"Hester","year":"2020","journal-title":"Vaccine"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1016\/j.intimp.2006.04.009","article-title":"Ginsenoside Rg1 Helps Mice Resist to Disseminated Candidiasis by Th1 Type Differentiation of CD4+ T Cell","volume":"6","author":"Lee","year":"2006","journal-title":"Int. Immunopharmacol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"3834","DOI":"10.1016\/j.vaccine.2007.01.108","article-title":"Immunoregulatory Activity by Daucosterol, a Beta-Sitosterol Glycoside, Induces Protective Th1 Immune Response Against Disseminated Candidiasis in Mice","volume":"25","author":"Lee","year":"2007","journal-title":"Vaccine"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01524","article-title":"Pathogenic Fungal Infection in the Lung","volume":"10","author":"Li","year":"2019","journal-title":"Front. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"7920","DOI":"10.4049\/jimmunol.174.12.7920","article-title":"Generation of Antifungal Effector CD8+ T Cells in the Absence of CD4+ T Cells During Cryptococcus Neoformans Infection","volume":"174","author":"Lindell","year":"2005","journal-title":"J. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"103864","DOI":"10.1016\/j.micpath.2019.103864","article-title":"Modulation of Host Immune Status by Cryptococcus Co-Infection During HIV-1 Pathogenesis and its Impact on CD+4 Cell and Cytokines Environment","volume":"139","author":"Linyu","year":"2020","journal-title":"Microb. Pathog."},{"key":"B23","doi-asserted-by":"publisher","first-page":"349","DOI":"10.7164\/antibiotics.48.349","article-title":"The Discovery of Australifungin, a Novel Inhibitor of Sphinganine N-Acyltransferase From Sporormiella Australis. Producing Organism, Fermentation, Isolation, and Biological Activity","volume":"48","author":"Mandala","year":"1995","journal-title":"J. Antibiot (Tokyo)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.tim.2019.10.003","article-title":"Cryptococcus Neoformans","volume":"28","author":"Mayer","year":"2020","journal-title":"Trends Microbiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jof6030142","article-title":"Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway","volume":"6","author":"McEvoy","year":"2020","journal-title":"J. Fungi (Basel)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jof7040260","article-title":"Associations Between Cryptococcus Genotypes, Phenotypes, and Clinical Parameters of Human Disease: A Review","volume":"7","author":"Montoya","year":"2021","journal-title":"J. Fungi (Basel)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jof4030079","article-title":"Present and Future Therapy of Cryptococcus Infections","volume":"4","author":"Mourad","year":"2018","journal-title":"J. Fungi (Basel)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1016\/j.celrep.2018.01.035","article-title":"The Role of Ceramide Synthases in the Pathogenicity of Cryptococcus Neoformans","volume":"22","author":"Munshi","year":"2018","journal-title":"Cell Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.biopha.2018.10.075","article-title":"Fungal Vaccines, Mechanism of Actions and Immunology: A Comprehensive Review","volume":"109","author":"Nami","year":"2019","journal-title":"BioMed. Pharmacother."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e1002771","DOI":"10.1371\/journal.ppat.1002771","article-title":"Tc17 Cells Mediate Vaccine Immunity Against Lethal Fungal Pneumonia in Immune Deficient Hosts Lacking CD4+ T Cells","volume":"8","author":"Nanjappa","year":"2012","journal-title":"PloS Pathog."},{"key":"B31","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1172\/JCI58762","article-title":"Protective Antifungal Memory CD8(+) T Cells are Maintained in the Absence of CD4(+) T Cell Help and Cognate Antigen in Mice","volume":"122","author":"Nanjappa","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2020.581750","article-title":"Animal Models of Cryptococcus Neoformans in Identifying Immune Parameters Associated With Primary Infection and Reactivation of Latent Infection","volume":"11","author":"Normile","year":"2020","journal-title":"Front. Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jof6010025","article-title":"Steryl Glycosides in Fungal Pathogenesis: An Understudied Immunomodulatory Adjuvant","volume":"6","author":"Normile","year":"2020","journal-title":"J. Fungi (Basel)"},{"key":"B34","doi-asserted-by":"publisher","first-page":"110550","DOI":"10.1016\/j.biopha.2020.110550","article-title":"Immune Defence to Invasive Fungal Infections: A Comprehensive Review","volume":"130","author":"Pathakumari","year":"2020","journal-title":"BioMed. Pharmacother."},{"key":"B35","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global Burden of Disease of HIV-Associated Cryptococcal Meningitis: An Updated Analysis","volume":"17","author":"Rajasingham","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fmicb.2015.00836","article-title":"Role of Sterylglucosidase 1 (Sgl1) on the Pathogenicity of Cryptococcus Neoformans: Potential Applications for Vaccine Development","volume":"6","author":"Rella","year":"2015","journal-title":"Front. Microbiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/978-1-4939-3804-9_12","article-title":"Analysis of Yeast Extracellular Vesicles","volume":"1459","author":"Rodrigues","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.00036","article-title":"Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis","volume":"8","author":"Scorzoni","year":"2017","journal-title":"Front. Microbiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/s10156-005-0387-X","article-title":"Granuloma and Cryptococcosis","volume":"11","author":"Shibuya","year":"2005","journal-title":"J. Infect. Chemother."},{"key":"B40","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1007\/978-1-61779-086-7_16","article-title":"Quantitation of Cellular Components in Cryptococcus Neoformans for System Biology Analysis","volume":"734","author":"Singh","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"25562","DOI":"10.1038\/srep25562","article-title":"Silencing of Sterol Glycosyltransferases Modulates the Withanolide Biosynthesis and Leads to Compromised Basal Immunity of Withania Somnifera","volume":"6","author":"Singh","year":"2016","journal-title":"Sci. Rep."},{"key":"B42","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.enzmictec.2013.02.004","article-title":"Characterization of Sterol Glucosyltransferase From Salinispora Tropica CNB-440: Potential Enzyme for the Biosynthesis of Sitosteryl Glucoside","volume":"52","author":"Thuan","year":"2013","journal-title":"Enzyme Microb. Technol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1248\/bpb.b19-00841","article-title":"Vaccines and Protective Immune Memory Against Cryptococcosis","volume":"43","author":"Ueno","year":"2020","journal-title":"Biol. Pharm. Bull."},{"key":"B44","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.msard.2016.06.007","article-title":"Cryptococcal Meningitis After Fingolimod Discontinuation in a Patient With Multiple Sclerosis","volume":"9","author":"Ward","year":"2016","journal-title":"Mult Scler Relat. Disord."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.739027\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T05:05:05Z","timestamp":1631077505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.739027\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,8]]},"references-count":44,"alternative-id":["10.3389\/fcimb.2021.739027"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2021.739027","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,8]]},"article-number":"739027"}}