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Drug-resistant strains add to the urgency for alternative therapies. In this context, vaccination has reemerged as a prominent immune-based strategy. Extracellular vesicles (EVs), nanosized lipid bilayer particles, carry a diverse array of native fungal antigens, including proteins, nucleic acids, lipids, and glycans. Previous studies from our laboratory demonstrated that\n              <jats:italic>Candida albicans<\/jats:italic>\n              EVs triggered the innate immune response, activating bone marrow-derived dendritic cells (BMDCs) and potentially acting as a bridge between innate and adaptive immunity. Vaccination with\n              <jats:italic>C. albicans<\/jats:italic>\n              EVs induced the production of specific antibodies, modulated cytokine production, and provided protection in immunosuppressed mice infected with lethal\n              <jats:italic>C. albicans<\/jats:italic>\n              inoculum. To elucidate the mechanisms underlying EV-induced immune activation, our study investigated pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) involved in EVs-phagocyte engagement. EVs from wild-type and mutant\n              <jats:italic>C. albicans<\/jats:italic>\n              strains with truncated mannoproteins were compared for their ability to stimulate BMDCs. Our findings revealed that EV decoration with\n              <jats:italic>O<\/jats:italic>\n              - and\n              <jats:italic>N<\/jats:italic>\n              -linked mannans and the presence of\n              <jats:italic>\u03b2<\/jats:italic>\n              -1,3-glucans and chitin oligomers may modulate the activation of specific PRRs, in particular Toll-like receptor 4 (TLR4) and dectin-1. The protective effect of vaccination with wild-type EVs was found to be dependent on TLR4. These results suggest that fungal EVs can be harnessed in vaccine formulations to selectively activate PRRs in phagocytes, offering potential avenues for combating or preventing candidiasis.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                Systemic candidiasis is a serious global health concern with high mortality rates and growing drug resistance. Vaccination offers a promising solution. A unique approach involves using tiny lipid-coated particles called extracellular vesicles (EVs), which carry various fungal components. Previous studies found that\n                <jats:italic>Candida albicans<\/jats:italic>\n                EVs activate the immune response and may bridge the gap between innate and adaptive immunity. To understand this better, we investigated how these EVs activate immune cells. We demonstrated that specific components on EV surfaces, such as mannans and glucans, interact with receptors on immune cells, including Toll-like receptor 4 (TLR4) and dectin-1. Moreover, vaccinating with these EVs led to strong immune responses and full protection in mice infected with\n                <jats:italic>Candida<\/jats:italic>\n                . This work shows how harnessing fungal EVs might lead to effective vaccines against candidiasis.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/msphere.00467-24","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T13:00:21Z","timestamp":1721653221000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["Toll-like receptor 4 (TLR4) is the major pattern recognition receptor triggering the protective effect of a\n            <i>Candida albicans<\/i>\n            extracellular vesicle-based vaccine prototype in murine systemic candidiasis"],"prefix":"10.1128","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0370-5682","authenticated-orcid":false,"given":"Leandro","family":"Honorato","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Glicobiologia de Eucariotos, Departamento de Microbiologia Geral, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhon J. Artunduaga","family":"Bonilla","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Glicobiologia de Eucariotos, Departamento de Microbiologia Geral, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro F.","family":"Valdez","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Glicobiologia de Eucariotos, Departamento de Microbiologia Geral, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Frases","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biof\u00edsica de Fungos, Instituto de Biof\u00edsica Carlos Chagas Filhos (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"},{"name":"Rede Micologia, RJ, FAPERJ, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glauber Ribeiro de Sousa","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biof\u00edsica de Fungos, Instituto de Biof\u00edsica Carlos Chagas Filhos (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albaniza Liuane Ribeiro do Nascimento","family":"Sabino","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Glicobiologia de Eucariotos, Departamento de Microbiologia Geral, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia Martins","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Glicobiologia de Eucariotos, Departamento de Microbiologia Geral, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Glicobiologia de Eucariotos, Departamento de Microbiologia Geral, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina da Silva","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica e Imunologia das Micoses, Departamento de Microbiologia e Parasitologia, Instituto Biom\u00e9dico, Universidade Federal Fluminense, Niter\u00f3i, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Kornetz","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Glicobiologia de Eucariotos, Departamento de Microbiologia Geral, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6081-3439","authenticated-orcid":false,"given":"Marcio L.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Instituto de Microbiologia Paulo de G\u00f3es, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"},{"name":"Instituto Carlos Chagas (ICC), Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ), Curitiba, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2776-5850","authenticated-orcid":false,"given":"Neil A. 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