RESUMO

Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by the dimorphic fungus Paracoccidioides brasiliensis. Anti-PCM vaccine formulations based on the secreted fungal cell wall protein (gp43) or the derived P10 sequence containing a CD4(+) T-cell-specific epitope have shown promising results. In the present study, we evaluated new anti-PCM vaccine formulations based on the intranasal administration of P. brasiliensis gp43 or the P10 peptide in combination with the Salmonella enterica FliC flagellin, an innate immunity agonist binding specifically to the Toll-like receptor 5, in a murine model. BALB/c mice immunized with gp43 developed high-specific-serum immunoglobulin G1 responses and enhanced interleukin-4 (IL-4) and IL-10 levels. On the other hand, mice immunized with recombinant purified flagellins genetically fused with P10 at the central hypervariable domain, either flanked or not by two lysine residues, or the synthetic P10 peptide admixed with purified FliC elicited a prevailing Th1-type immune response based on lung cell-secreted type 1 cytokines. Mice immunized with gp43 and FliC and intratracheally challenged with P. brasiliensis yeast cells had increased fungal proliferation and lung tissue damage. In contrast, mice immunized with the chimeric flagellins and particularly those immunized with P10 admixed with FliC reduced P. brasiliensis growth and lung damage. Altogether, these results indicate that S. enterica FliC flagellin modulates the immune response to P. brasiliensis P10 antigen and represents a promising alternative for the generation of anti-PCM vaccines.

Assuntos

Antígenos de Fungos , Flagelina , Proteínas Fúngicas , Vacinas Fúngicas , Glicoproteínas , Paracoccidioides/imunologia , Paracoccidioidomicose/prevenção & controle , Peptídeos , Animais , Anticorpos Antibacterianos/sangue , Especificidade de Anticorpos , Antígenos de Fungos/química , Antígenos de Fungos/genética , Antígenos de Fungos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Flagelina/genética , Flagelina/imunologia , Flagelina/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/imunologia , Vacinas Fúngicas/administração & dosagem , Vacinas Fúngicas/genética , Vacinas Fúngicas/imunologia , Glicoproteínas/química , Glicoproteínas/genética , Glicoproteínas/imunologia , Humanos , Imunização , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Paracoccidioides/patogenicidade , Paracoccidioidomicose/imunologia , Paracoccidioidomicose/microbiologia , Peptídeos/síntese química , Peptídeos/genética , Peptídeos/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Salmonella enterica/genética , Salmonella enterica/imunologia , Salmonella enterica/metabolismo