{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T21:13:18Z","timestamp":1766869998211},"reference-count":67,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T00:00:00Z","timestamp":1675123200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de S\u00e3o Paulo","award":["2018\/18538-0","2018\/19949-4","2019\/09260-1","2019\/09261-8","2019\/26074-7","2021\/02758-4"],"award-info":[{"award-number":["2018\/18538-0","2018\/19949-4","2019\/09260-1","2019\/09261-8","2019\/26074-7","2021\/02758-4"]}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["431853\/2018-5"],"award-info":[{"award-number":["431853\/2018-5"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n               <jats:title>Background<\/jats:title>\n               <jats:p>Cryptococcosis is a relevant invasive fungal infection that affects immunocompromised and immunocompetent individuals when caused by <jats:italic>Cryptococcus gattii<\/jats:italic>. Host innate and adaptive immune responses can be subverted by <jats:italic>C. gattii,<\/jats:italic> that blocks the differentiation of T helper (Th) 1 and Th17 cells, which are involved in the protection against cryptococcosis. Moreover, the macrophage polarization is modulated by <jats:italic>C. gattii<\/jats:italic> infection that requires a balance in the macrophage subsets to control the <jats:italic>C. gattii<\/jats:italic> infection. Toll-like receptor (TLR) 2 agonists are important immunomodulators favoring a pro-inflammatory response with potential fungicidal activity, and TLR2 agonists have been used as adjuvants in vaccines against infections caused by bacteria or viruses. Therefore, this work aimed to evaluate the immunomodulatory effect of the tripalmitoyl lipopeptide S-glycerol cysteine (Pam3CSK4 or P3C4), a TLR2 agonist, as an adjuvant in the vaccination against <jats:italic>C. gattii<\/jats:italic> infection.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Methods and Results<\/jats:title>\n               <jats:p>C57BL\/6 mice were immunized with 2\u00a0\u00d7\u00a010<jats:sup>7<\/jats:sup> inactivated yeasts of <jats:italic>C. gattii<\/jats:italic> via intranasal route on day 1, 14 and 28 (Immunized group). Immunization was associated with 1\u00b5g or 10\u00b5g of adjuvant P3C4 (Immunized+P3C4-1\u00b5g or Immunized+P3C4-10\u00a0\u00b5g), followed by <jats:italic>C. gattii<\/jats:italic> infection on day 42 after the immunization protocol. Immunized+P3C4-1\u00a0\u00b5g group had reduced levels of IgG1, IgG2a and IgA and no significant difference in the IgG and IgM anti-GXM antibody titer was detected, compared to the Immunized group. High levels of IL-17 and IL-1<jats:italic>\u03b2<\/jats:italic> in lung tissue of mice from the Immunized+P3C4-1\u00b5g group did not promote a predominance of Th17 cells, in contrast, the frequency of TLR2<jats:sup>+<\/jats:sup> cells was increased in immunized mice that received 1 \u00b5g of P3C4. The reduction in the relative expression of T-bet and high levels of Foxp3 detected in the lungs of the Immunized+P3C4-1\u00b5g group suggest a prevalence of regulatory T cells in the tissue, which did not contribute to the control of <jats:italic>C. gattii<\/jats:italic> infection. The immunization protocol associated with 10 \u00b5g of adjuvant P3C4 induced high levels of IL-17 in the lung tissue, whereas the levels of pro-inflammatory cytokines were downregulated. To evaluate the effect of adjuvant P3C4 in the control of <jats:italic>C. gattii<\/jats:italic> infection, quantification of the fungal burden in the lungs was performed by the CFU assay, and the groups with adjuvant P3C4 showed a pulmonary <jats:italic>C. gattii<\/jats:italic> burden that was not significantly altered when compared with the immunized group. The mice that received 1 \u00b5g of adjuvant P3C4 had a lower percentage of inflammatory infiltrate in the lungs.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Conclusion<\/jats:title>\n               <jats:p>The immunomodulatory effect of P3C4, associated with the immunization protocol, plays an imbalance between pro- and anti-inflammatory response in the lungs that did not favor a protection against <jats:italic>C. gattii<\/jats:italic> infection, which is related to the immune response characterized by a suppressive\/regulatory profile in the pulmonary microenvironment after <jats:italic>C. gattii<\/jats:italic> infection.<\/jats:p>\n            <\/jats:sec>","DOI":"10.7717\/peerj.14778","type":"journal-article","created":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T10:40:44Z","timestamp":1675161644000},"page":"e14778","source":"Crossref","is-referenced-by-count":3,"title":["Adjuvant Pam3CSk4 does not improve the immunization against <i>Cryptococcus gattii<\/i> infection in C57BL\/6 mice"],"prefix":"10.7717","volume":"11","author":[{"given":"Gabriela Yamazaki","family":"de Campos","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patr\u00edcia Kellen Martins","family":"Oliveira-Brito","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00falia Garcia","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Let\u00edcia Serafim","family":"da Costa","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier Em\u00edlio","family":"Lazo Chica","sequence":"additional","affiliation":[{"name":"Institute of Natural and Biological Sciences, Federal University of Tri\u00e2ngulo Mineiro, Uberaba, Minas Gerais, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thiago Aparecido","family":"da Silva","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"4443","published-online":{"date-parts":[[2023,1,31]]},"reference":[{"issue":"6797","key":"10.7717\/peerj.14778\/ref-1","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1038\/35021228","article-title":"Toll-like 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