{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:35:21Z","timestamp":1793140521353,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006507","name":"Funda\u00c3\u00a7\u00c3\u00a3o Oswaldo Cruz","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006507","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00c3\u00adfico e Tecnol\u00c3\u00b3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00c3\u00a7\u00c3\u00a3o de Aperfei\u00c3\u00a7oamento de Pessoal de N\u00c3\u00advel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006506","name":"Minist\u00c3\u00a9rio da Sa\u00c3\u00bade","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006506","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The small molecule (molecular mass &amp;lt;900 Daltons) composition of extracellular vesicles (EVs) produced by the pathogenic fungus\n                    <jats:italic>Cryptococcus gattii<\/jats:italic>\n                    is unknown, which limits the understanding of the functions of cryptococcal EVs. In this study, we analyzed the composition of small molecules in samples obtained from solid cultures of\n                    <jats:italic>C. gattii<\/jats:italic>\n                    by a combination of chromatographic and spectrometric approaches, and untargeted metabolomics. This analysis revealed previously unknown components of EVs, including small peptides with known biological functions in other models. The peptides found in\n                    <jats:italic>C. gattii<\/jats:italic>\n                    EVs had their chemical structure validated by chemical approaches and comparison with authentic standards, and their functions tested in a\n                    <jats:italic>Galleria mellonella<\/jats:italic>\n                    model of cryptococcal infection. One of the vesicular peptides (isoleucine-proline-isoleucine, Ile-Pro-Ile) improved the survival of\n                    <jats:italic>G. mellonella<\/jats:italic>\n                    lethally infected with\n                    <jats:italic>C. gattii<\/jats:italic>\n                    or\n                    <jats:italic>C. neoformans<\/jats:italic>\n                    . These results indicate that small molecules exported in EVs are biologically active in\n                    <jats:italic>Cryptococcus<\/jats:italic>\n                    . Our study is the first to characterize a fungal EV molecule inducing protection, pointing to an immunological potential of extracellular peptides produced by\n                    <jats:italic>C. gattii<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2021.654574","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T02:52:17Z","timestamp":1615863137000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Small Molecule Analysis of Extracellular Vesicles Produced by Cryptococcus gattii: Identification of a Tripeptide Controlling Cryptococcal Infection in an Invertebrate Host Model"],"prefix":"10.3389","volume":"12","author":[{"given":"Flavia C. G.","family":"Reis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas H.","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro","family":"Honorato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Nimrichter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ta\u00edcia P.","family":"Fill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcio L.","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"a019760","DOI":"10.1101\/cshperspect.a019760","article-title":"Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis","volume":"4","author":"Kwon-Chung","year":"2014","journal-title":"Cold Spring Harb Perspect Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e0197841","DOI":"10.1371\/journal.pone.0197841","article-title":"MLST reveals a clonal population structure for Cryptococcus neoformans molecular type VNI isolates from clinical sources in Amazonas, Northern-Brazil","volume":"13","author":"Rocha","year":"2018","journal-title":"PLoS ONE."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e71148","DOI":"10.1371\/journal.pone.0071148","article-title":"Ancient dispersal of the human fungal pathogen Cryptococcus gattii from the Amazon rainforest","volume":"8","author":"Hagen","year":"2013","journal-title":"PLoS ONE."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.1038\/s41467-018-03991-6","article-title":"Pathogen-derived extracellular vesicles mediate virulence in the fatal human pathogen Cryptococcus gattii","volume":"9","author":"Bielska","year":"2018","journal-title":"Nat Commun"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e00080","DOI":"10.1128\/mSphere.00080-19","article-title":"A novel protocol for the isolation of fungal extracellular vesicles reveals the participation of a putative scramblase in polysaccharide export and capsule construction in Cryptococcus gattii","volume":"4","author":"Reis","year":"2019","journal-title":"mSphere"},{"key":"B6","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1128\/EC.00318-06","article-title":"Vesicular polysaccharide export in Cryptococcus neoformans is a eukaryotic solution to the problem of fungal trans-cell wall transport","volume":"6","author":"Rodrigues","year":"2007","journal-title":"Eukaryot Cell."},{"key":"B7","doi-asserted-by":"publisher","first-page":"346","DOI":"10.3389\/fcimb.2020.00346","article-title":"Extracellular vesicles in fungi: past, present, and future perspectives","volume":"10","author":"Rizzo","year":"2020","journal-title":"Front Cell Infect Microbiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.jprot.2013.04.001","article-title":"The impact of proteomics on the understanding of functions and biogenesis of fungal extracellular vesicles","volume":"97","author":"Rodrigues","year":"2014","journal-title":"J Proteomics."},{"key":"B9","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/82_2018_141","article-title":"Extracellular vesicles in fungi: composition and functions","volume":"422","author":"de Toledo Martins","year":"2019","journal-title":"Curr Top Microbiol Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e13217","DOI":"10.1111\/cmi.13217","article-title":"Media matters! alterations in the loading and release of histoplasma capsulatum extracellular vesicles in response to different nutritional milieus","volume":"22","author":"Cleare","year":"2020","journal-title":"Cell Microbiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e03393","DOI":"10.1128\/mBio.03393-20","article-title":"Phytotoxic tryptoquialanines produced in vivo by penicillium digitatum are exported in extracellular vesicles","volume":"12","author":"Costa","year":"2021","journal-title":"mBio."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1101\/2020.08.17.253716","article-title":"New insights into Cryptococcus extracellular vesicles suggest a new structural model and an antifungal vaccine strategy","author":"Rizzo","year":"2020","journal-title":"bioRxiv."},{"key":"B13","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1128\/EC.00370-07","article-title":"Extracellular vesicles produced by Cryptococcus neoformans contain protein components associated with virulence","volume":"7","author":"Rodrigues","year":"2008","journal-title":"Eukaryot Cell."},{"key":"B14","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1038\/nbt.3597","article-title":"Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking","volume":"34","author":"Wang","year":"2016","journal-title":"Nat Biotechnol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1039\/c3np70127a","article-title":"Secondary metabolomics: the impact of mass spectrometry-based approaches on the discovery and characterization of microbial natural products","volume":"31","author":"Krug","year":"2014","journal-title":"Nat Prod Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3390\/metabo6010002","article-title":"Using molecular networking for microbial secondary metabolite bioprospecting","volume":"6","author":"Purves","year":"2016","journal-title":"Metabolites."},{"key":"B17","doi-asserted-by":"publisher","first-page":"E1743","DOI":"10.1073\/pnas.1203689109","article-title":"Mass spectral molecular networking of living microbial colonies","volume":"109","author":"Watrous","year":"2012","journal-title":"Proc Natl Acad Sci USA."},{"key":"B18","doi-asserted-by":"publisher","first-page":"E2611","DOI":"10.1073\/pnas.1303471110","article-title":"MS\/MS networking guided analysis of molecule and gene cluster families","volume":"110","author":"Nguyen","year":"2013","journal-title":"Proc Natl Acad Sci USA."},{"key":"B19","doi-asserted-by":"publisher","first-page":"6453","DOI":"10.1038\/s41598-019-42777-8","article-title":"Revisiting fragmentation reactions of protonated \u03b1-amino acids by high-resolution electrospray ionization tandem mass spectrometry with collision-induced dissociation","volume":"9","author":"Zhang","year":"2019","journal-title":"Sci Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41396-018-0293-8","article-title":"Induction of antibacterial proteins and peptides in the coprophilous mushroom Coprinopsis cinerea in response to bacteria","volume":"13","author":"Kombrink","year":"2019","journal-title":"ISME J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e13238","DOI":"10.1111\/cmi.13238","article-title":"Protective effect of fungal extracellular vesicles against murine candidiasis","volume":"22","author":"Vargas","year":"2020","journal-title":"Cell Microbiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e02909","DOI":"10.1128\/mBio.02909-18","article-title":"Cryptococcus neoformans glucuronoxylomannan and sterylglucoside are required for host protection in an animal vaccination model","volume":"10","author":"Colombo","year":"2019","journal-title":"mBio."},{"key":"B23","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1111\/cmi.12374","article-title":"Compositional and immunobiological analyses of extracellular vesicles released by Candida albicans","volume":"17","author":"Vargas","year":"2015","journal-title":"Cell Microbiol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3412763","DOI":"10.1155\/2020\/3412763","article-title":"Cryptococcus neoformans secretes small molecules that inhibit IL-1\u03b2 inflammasome-dependent secretion","volume":"2020","author":"B\u00fcrgel","year":"2020","journal-title":"Mediators Inflamm."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e01017","DOI":"10.1128\/mBio.01017-15","article-title":"Sup35p in its soluble and prion states is packaged inside extracellular vesicles","volume":"6","author":"Kabani","year":"2015","journal-title":"mBio."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e2006872","DOI":"10.1371\/journal.pbio.2006872","article-title":"Candida albicans biofilm-induced vesicles confer drug resistance through matrix biogenesis","volume":"16","author":"Zarnowski","year":"2018","journal-title":"PLoS Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1128\/IAI.01171-09","article-title":"Extracellular vesicles from Cryptococcus neoformans modulate macrophage functions","volume":"78","author":"Oliveira","year":"2010","journal-title":"Infect Immun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"35867","DOI":"10.1038\/srep35867","article-title":"Extracellular vesicles from Paracoccidioides brasiliensis induced M1 polarization in vitro","volume":"6","author":"da Silva","year":"2016","journal-title":"Sci Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2343","DOI":"10.3389\/fimmu.2018.02343","article-title":"Extracellular vesicles from the dermatophyte trichophyton interdigitale modulate macrophage and keratinocyte functions","volume":"9","author":"Bitencourt","year":"2018","journal-title":"Front Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1968","DOI":"10.1038\/s41467-017-02126-7","article-title":"Galectin-3 impacts Cryptococcus neoformans infection through direct antifungal effects","volume":"8","author":"Almeida","year":"2017","journal-title":"Nat Commun."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1750810","DOI":"10.1080\/20013078.2020.1750810","article-title":"Protein markers for Candida albicans EVs include claudin-like Sur7 family proteins","volume":"9","author":"Dawson","year":"2020","journal-title":"J Extracell Vesicles."},{"key":"B32","doi-asserted-by":"publisher","first-page":"7763","DOI":"10.1038\/srep07763","article-title":"Extracellular vesicle-mediated export of fungal RNA","volume":"5","author":"Peres da Silva","year":"2015","journal-title":"Sci Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3390\/jof5010003","article-title":"Immune response of galleria mellonella against human fungal pathogens","volume":"5","author":"Trevijano-Contador","year":"2018","journal-title":"J Fungi."},{"key":"B34","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.fgb.2014.11.006","article-title":"Immunity to Cryptococcus neoformans and C. gattii during cryptococcosis","volume":"78","author":"Gibson","year":"2015","journal-title":"Fungal Genet Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1111\/j.1365-2141.2005.05397.x","article-title":"The immune response to fungal infections","volume":"129","author":"Shoham","year":"2005","journal-title":"Br J Haematol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"3585","DOI":"10.1210\/endo.136.8.7628397","article-title":"Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV","volume":"136","author":"Kieffer","year":"1995","journal-title":"Endocrinology."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1634\/stemcells.2005-0085","article-title":"SDF-1\/CXCL12 enhances survival and chemotaxis of murine embryonic stem cells and production of primitive and definitive hematopoietic progenitor cells","volume":"23","author":"Guo","year":"2005","journal-title":"Stem Cells."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3042","DOI":"10.1128\/IAI.65.8.3042-3047.1997","article-title":"Dipeptidyl-peptidase IV secreted by Aspergillus fumigatus, a fungus pathogenic to humans","volume":"65","author":"Beauvais","year":"1997","journal-title":"Infect Immun."},{"key":"B39","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.chom.2016.02.001","article-title":"Fungal mimicry of a mammalian aminopeptidase disables innate immunity and promotes pathogenicity","volume":"19","author":"Sterkel","year":"2016","journal-title":"Cell Host Microbe."},{"key":"B40","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.fgb.2015.02.009","article-title":"Recognition of seven species in the Cryptococcus gattii\/Cryptococcus neoformans species complex","volume":"78","author":"Hagen","year":"2015","journal-title":"Fungal Genet Biol."}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.654574\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T02:52:20Z","timestamp":1615863140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.654574\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,16]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2021.654574"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.654574","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.01.18.427068","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,16]]},"article-number":"654574"}}