{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:40:43Z","timestamp":1787942443215,"version":"build-2784847793"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX000656, IK6BX003615\u201001 , IK2BX006208"],"award-info":[{"award-number":["I01BX000656, IK6BX003615\u201001 , IK2BX006208"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI73896 , AI93257 , 5T32HL007749-27"],"award-info":[{"award-number":["R01AI73896 , AI93257 , 5T32HL007749-27"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002590","name":"American Lung Association","doi-asserted-by":"publisher","award":["CA-827199"],"award-info":[{"award-number":["CA-827199"]}],"id":[{"id":"10.13039\/100002590","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for <jats:italic>Cryptococcus neoformans<\/jats:italic> and a promising therapeutic target. This study reveals previously unknown roles of TPS1 in evasion of host defenses during pulmonary and disseminated phases of infection. In the pulmonary infection model, TPS1-deleted (<jats:italic>tps1\u0394<\/jats:italic>) <jats:italic>Cryptococci<\/jats:italic> are rapidly cleared by mouse lungs whereas TPS1-sufficent WT (H99) and revertant (<jats:italic>tps1\u0394<\/jats:italic>:<jats:italic>TPS1<\/jats:italic>) strains expand in the lungs and disseminate, causing 100% mortality. Rapid pulmonary clearance of <jats:italic>tps1\u0394<\/jats:italic> mutant is T-cell independent and relies on its susceptibility to lung resident factors and innate immune factors, exemplified by <jats:italic>tps1\u0394<\/jats:italic> but not H99 inhibition in a coculture with dispersed lung cells and its rapid clearance coinciding with innate leukocyte infiltration. In the disseminated model of infection, which bypasses initial lung\u2013fungus interactions, <jats:italic>tps1\u0394<\/jats:italic> strain remains highly attenuated. Specifically, <jats:italic>tps1\u0394<\/jats:italic> mutant is unable to colonize the lungs from the bloodstream or expand in spleens but is capable of crossing into the brain, where it remains controlled even in the absence of T cells. In contrast, strains H99 and <jats:italic>tps1\u0394:TPS1<\/jats:italic> rapidly expand in all studied organs, leading to rapid death of the infected mice. Since the rapid pulmonary clearance of <jats:italic>tps1\u0394<\/jats:italic> mutant resembles a response to acapsular strains, the effect of <jats:italic>tps1<\/jats:italic> deletion on capsule formation <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> was examined. <jats:italic>Tps1\u0394<\/jats:italic> cryptococci form capsules but with a substantially reduced size. In conclusion, TPS1 is an important virulence factor, allowing <jats:italic>C. neoformans<\/jats:italic> evasion of resident pulmonary and innate defense mechanisms, most likely <jats:italic>via<\/jats:italic> its role in cryptococcal capsule formation.<\/jats:p>","DOI":"10.3389\/fcimb.2024.1392015","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T04:37:55Z","timestamp":1716352675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Cryptococcus neoformans trehalose-6-phosphate synthase (tps1) promotes organ-specific virulence and fungal protection against multiple lines of host defenses"],"prefix":"10.3389","volume":"14","author":[{"given":"Kristie","family":"Goughenour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Creech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumiao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rylan","family":"Hissong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Giamberardino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Tenor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dena","family":"Toffaletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Perfect","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Olszewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3007","DOI":"10.1128\/IAI.00813-09","article-title":"Role of trehalose biosynthesis in Aspergillus fumigatus development, stress response, and virulence","volume":"78","author":"Al-Bader","year":"2010","journal-title":"Infect. Immun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1007\/s10096-008-0529-z","article-title":"Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease","volume":"27","author":"Baddley","year":"2008","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.mib.2017.10.012","article-title":"The cause and effect of Cryptococcus interactions with the host","volume":"40","author":"Ballou","year":"2017","journal-title":"Curr. Opin. Microbiol."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/jof3040057","article-title":"Global and multi-national prevalence of fungal diseases\u2014Estimate precision","volume":"3","author":"Bongomin","year":"2017","journal-title":"J. Fungi (Basel)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1080\/21505594.2018.1431087","article-title":"The capsule of Cryptococcus neoformans","volume":"10","author":"Casadevall","year":"2019","journal-title":"Virulence"},{"key":"B6","doi-asserted-by":"publisher","first-page":"4912","DOI":"10.1128\/mcb.14.7.4912-4919.1994","article-title":"Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence","volume":"14","author":"Chang","year":"1994","journal-title":"Mol. Cell Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.1128\/IAI.66.5.2230-2236.1998","article-title":"Isolation of the third capsule-associated gene, CAP60, required for virulence in Cryptococcus neoformans","volume":"66","author":"Chang","year":"1998","journal-title":"Infect. Immun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1128\/IAI.01143-07","article-title":"Inheritance of Immune Polarization Patterns Is Linked to Resistance versus Susceptibility to Cryptococcus neoformans in a Mouse Model","volume":"76","author":"Chen","year":"2008","journal-title":"Infection Immun."},{"key":"B9","doi-asserted-by":"publisher","first-page":"261","DOI":"10.3109\/13693786.2012.715763","article-title":"Fluconazole resistance in cryptococcal disease: emerging or intrinsic","volume":"51","author":"Cheong","year":"2013","journal-title":"Med. Mycology"},{"key":"B10","first-page":"113","article-title":"Experimental murine pulmonary cryptococcosis. Differences in pulmonary inflammation and lymphocyte recruitment induced by two encapsulated strains of Cryptococcus neoformans","volume":"71","author":"Curtis","year":"1994","journal-title":"Lab. Invest."},{"key":"B11","doi-asserted-by":"publisher","first-page":"5999","DOI":"10.4049\/jimmunol.1402719","article-title":"Cryptococcal heat shock protein 70 homolog Ssa1 contributes to pulmonary expansion of Cryptococcus neoformans during the afferent phase of the immune response by promoting macrophage M2 polarization","volume":"194","author":"Eastman","year":"2015","journal-title":"J. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/BF00636177","article-title":"Decreased virulence in stable, acapsular mutants of cryptococcus neoformans","volume":"79","author":"Fromtling","year":"1982","journal-title":"Mycopathologia"},{"key":"B13","doi-asserted-by":"publisher","first-page":"3523","DOI":"10.2741\/3468","article-title":"Thermodynamic, hydration and structural characteristics of alpha,alpha-trehalose","volume":"14","author":"Furuki","year":"2009","journal-title":"Front. Biosci. (Landmark Ed)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"3204","DOI":"10.1128\/JCM.37.10.3204-3209.1999","article-title":"Epidemiological evidence for dormant Cryptococcus neoformans infection","volume":"37","author":"Garcia-Hermoso","year":"1999","journal-title":"J. Clin. Microbiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1128\/IAI.68.2.832-838.2000","article-title":"Persistent Cryptococcus neoformans pulmonary infection in the rat is associated with intracellular parasitism, decreased inducible nitric oxide synthase expression, and altered antibody responsiveness to cryptococcal polysaccharide","volume":"68","author":"Goldman","year":"2000","journal-title":"Infect. Immun."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2096","DOI":"10.4049\/jimmunol.2100386","article-title":"Murine Inducible Nitric Oxide Synthase Expression Is Essential for Antifungal Defenses in Kidneys during Disseminated Cryptococcus deneoformans Infection","volume":"207","author":"Goughenour","year":"2021","journal-title":"J. Immunol."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.872286","article-title":"Cryptococcus neoformans infection induces IL-17 production by promoting STAT3 phosphorylation in CD4+ T cells","volume":"13","author":"Guo","year":"2022","journal-title":"Front. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"425","DOI":"10.30802\/AALAS-CM-18-000049","article-title":"Effects of rodent thermoregulation on animal models in the research environment","volume":"68","author":"Hankenson","year":"2018","journal-title":"Comp. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/S0923-2494(98)80762-1","article-title":"Cells and cytokines in pulmonary cryptococcosis","volume":"149","author":"Huffnagle","year":"1998","journal-title":"Res. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4529","DOI":"10.4049\/jimmunol.157.10.4529","article-title":"Afferent phase production of TNF-alpha is required for the development of protective T cell immunity to Cryptococcus neoformans","volume":"157","author":"Huffnagle","year":"1996","journal-title":"J. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1084\/jem.173.4.793","article-title":"Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells","volume":"173","author":"Huffnagle","year":"1991","journal-title":"J. Exp. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1080\/21505594.2016.1276692","article-title":"The unmet clinical need of novel antifungal drugs","volume":"8","author":"Krysan","year":"2017","journal-title":"Virulence"},{"key":"B23","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1128\/EC.00290-13","article-title":"Pbx proteins in Cryptococcus neoformans cell wall remodeling and capsule assembly","volume":"13","author":"Kumar","year":"2014","journal-title":"Eukaryot Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1128\/iai.30.1.5-11.1980","article-title":"Transfer of immunity to cryptococcosis by T-enriched splenic lymphocytes from Cryptococcus neoformans-sensitized mice","volume":"30","author":"Lim","year":"1980","journal-title":"Infect. Immun."},{"key":"B25","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1007\/s12010-016-2258-6","article-title":"Trehalose-6-phosphate as a potential lead candidate for the development of tps1 inhibitors: insights from the trehalose biosynthesis pathway in diverse yeast species","volume":"181","author":"Magalh\u00e3es","year":"2017","journal-title":"Appl. Biochem. Biotechnol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1111\/j.1469-0691.2007.01663.x","article-title":"Role of trehalose in resistance to macrophage killing: study with a tps1\/tps1 trehalose-deficient mutant of Candida albicans","volume":"13","author":"Mart\u00ednez-Esparza","year":"2007","journal-title":"Clin. Microbiol. Infection"},{"key":"B27","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nrmicro.2015.6","article-title":"Cryptococcus: from environmental saprophyte to global pathogen","volume":"14","author":"May","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"B28","unstructured":"\u201cAntifungal antibiotics,\u201d\n            McKenyP. T.\n            NesselT. A.\n            ZitoP. M.\n          Treasure Island (FLStatPearls PublishingStatPearls2022"},{"key":"B29","first-page":"765","article-title":"Depletion of murine CD8+ T cells in vivo decreases pulmonary clearance of a moderately virulent strain of Cryptococcus neoformans","volume":"121","author":"Mody","year":"1993","journal-title":"J. Lab. Clin. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1472","DOI":"10.4049\/jimmunol.144.4.1472","article-title":"Depletion of CD4+ (L3T4+) lymphocytes in vivo impairs murine host defense to Cryptococcus neoformans","volume":"144","author":"Mody","year":"1990","journal-title":"J. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"7202","DOI":"10.1038\/s41467-023-43061-0","article-title":"Microglia are not protective against cryptococcal meningitis","volume":"14","author":"Mohamed","year":"2023","journal-title":"Nat. Commun."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01415-17","article-title":"CD4+ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis","volume":"8","author":"Neal","year":"2017","journal-title":"mBio"},{"key":"B33","doi-asserted-by":"publisher","first-page":"4584","DOI":"10.1128\/IAI.00565-09","article-title":"The trehalose synthesis pathway is an integral part of the virulence composite for Cryptococcus gattii","volume":"77","author":"Ngamskulrungroj","year":"2009","journal-title":"Infect. Immun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3749","DOI":"10.1128\/IAI.00454-09","article-title":"Role of Dendritic Cells and Alveolar Macrophages in Regulating Early Host Defense against Pulmonary Infection with Cryptococcus neoformans","volume":"77","author":"Osterholzer","year":"2009","journal-title":"Infection Immun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"932","DOI":"10.2353\/ajpath.2009.080673","article-title":"Cryptococcal urease promotes the accumulation of immature dendritic cells and a non-protective T2 immune response within the lung","volume":"174","author":"Osterholzer","year":"2009","journal-title":"Am. J. Pathol."},{"key":"B36","first-page":"61","article-title":"Cryptococcal infections in non-HIV-infected patients","volume":"124","author":"Pappas","year":"2013","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"B37","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1086\/649858","article-title":"Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america","volume":"50","author":"Perfect","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1080\/21505594.2016.1195529","article-title":"Trehalose pathway as an antifungal target","volume":"8","author":"Perfect","year":"2016","journal-title":"Virulence"},{"key":"B39","doi-asserted-by":"publisher","first-page":"5877","DOI":"10.1128\/IAI.00624-06","article-title":"Characterization and regulation of the trehalose synthesis pathway and its importance in the pathogenicity of cryptococcus neoformans","volume":"74","author":"Petzold","year":"2006","journal-title":"Infect. Immun."},{"key":"B40","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":"B41","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1046\/j.1365-2958.2003.03780.x","article-title":"Cell wall alpha-1,3-glucan is required to anchor the Cryptococcus neoformans capsule","volume":"50","author":"Reese","year":"2003","journal-title":"Mol. Microbiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1111\/j.1365-2958.2006.05551.x","article-title":"Loss of cell wall alpha(1\u20133) glucan affects Cryptococcus neoformans from ultrastructure to virulence","volume":"63","author":"Reese","year":"2007","journal-title":"Mol. Microbiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/S0278-6915(02)00011-X","article-title":"Trehalose: a review of properties, history of use and human tolerance, and results of multiple safety studies","volume":"40","author":"Richards","year":"2002","journal-title":"Food Chem. Toxicol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.tcsw.2018.05.002","article-title":"Lack of chitin synthase genes impacts capsular architecture and cellular physiology in Cryptococcus neoformans","volume":"2","author":"Rodrigues","year":"2018","journal-title":"Cell Surface"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a019703","article-title":"Antifungal drug development: challenges, unmet clinical needs, and new approaches","volume":"4","author":"Roemer","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e02253","DOI":"10.1128\/mbio.02253-22","article-title":"The cryptococcus neoformans flc1 homologue controls calcium homeostasis and confers fungal pathogenicity in the infected hosts","volume":"13","author":"Stempinski","year":"2022","journal-title":"mBio"},{"key":"B47","unstructured":"Merck Veterinary Manual"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e00053","DOI":"10.1128\/MMBR.00053-16","article-title":"Central role of the trehalose biosynthesis pathway in the pathogenesis of human fungal infections: opportunities and challenges for therapeutic development","volume":"81","author":"Thammahong","year":"2017","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41572-023-00472-z","article-title":"Cryptococcal meningitis","volume":"9","author":"Tugume","year":"2023","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/13693780500088424","article-title":"Role of CD4+ T cells in a protective immune response against Cryptococcus neoformans in the central nervous system","volume":"44","author":"Uicker","year":"2006","journal-title":"Med. Mycol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.14.530545","article-title":"Structures of trehalose-6-phosphate synthase, Tps1, from the fungal pathogen Cryptococcus neoformans: a target for novel antifungals","author":"Washington","year":"2023","journal-title":"bioRxiv"},{"key":"B52","unstructured":"2022"},{"key":"B53","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1128\/AAC.01624-12","article-title":"Limited activity of miltefosine in murine models of cryptococcal meningoencephalitis and disseminated cryptococcosis","volume":"57","author":"Wiederhold","year":"2013","journal-title":"Antimicrobial Agents Chemotherapy"},{"key":"B54","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.1128\/IAI.00094-07","article-title":"The relative susceptibility of mouse strains to pulmonary cryptococcus neoformans infection is associated with pleiotropic differences in the immune response","volume":"75","author":"Zaragoza","year":"2007","journal-title":"Infect. Immun."},{"key":"B55","doi-asserted-by":"publisher","first-page":"2489","DOI":"10.2353\/ajpath.2009.090530","article-title":"Robust Th1 and Th17 immunity supports pulmonary clearance but cannot prevent systemic dissemination of highly virulent Cryptococcus neoformans H99","volume":"175","author":"Zhang","year":"2009","journal-title":"Am J Pathol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2024.1392015\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T04:38:02Z","timestamp":1716352682000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2024.1392015\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,22]]},"references-count":55,"alternative-id":["10.3389\/fcimb.2024.1392015"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2024.1392015","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,22]]},"article-number":"1392015"}}