The systemic mycoses, including paracoccidioidomycosis (PCM), criptococcosis and histoplasmosis, among others, were the main cause of death in 3.583 individuals between 1996-2006 in Brazil. Of these, PCM was the most important cause with 51,2% of the deaths, followed by histoplasmosis with 4,8% of the deaths in non HIV-infected patients. Considering the patients with Aids as the main cause of death, and the systemic mycoses as co-morbidities, histoplasmosis appears in 10.1% of the cases and PCM with 1.4%. Antifungal drugs currently represent the best approach to treat the systemic mycoses. However, the patients frequently undergo prolonged antifungal regimens, and relapses, poor compliance and the advent of sequels are not uncommon. Vaccine models have been developed against aspergilosis, candidiasis, criptococosis, coccidioidomicosis and histoplasmosis have been reported, but a well established vaccine product and immunization protocol for clinical purposes have not been yet accomplished for any of them. Regarding PCM, our group have been working with a peptidic vaccine (P10), derived from a fraction of the immunodominant protein gp43 from Paracoccidioides brasiliensis. However, a mutation in the gp43 gene in the recently proposed new species of the genus Paracoccidioides, P. lutzii, precludes the use of the P10 in immunization strategies against PCM caused by this species. The present project encompasses different approaches to validate an immunization strategy to PCM: a subproject will address specifically the hostimmune response, such a as the function of neutrophils, macrophages, TCD4+/CD8+ lymphocytes and NK 1.1 cells in a n experimental model of infection with P. brasiliensis yeasts and conidia and prophylactic/therapeutic P10 vaccination, using mice strains with different susceptibility profiles to Paracoccidioides infection. A second project will address the development of vaccines and passive immunization protocols, focusing specifically in the cytotoxic and immune-stimulatory effects of the P10 in patients with PCM, the characterization of the modulatory activity induced by the dendritic cells of mice infected with virulent isolates of Paracoccidioides spp. in the presence/absence of antifungal drugs, evaluate the performance of antigens and antibodies against P. lutzii aiming at designing a vaccine tool to this species, and identify epitope(s) to be used in the development of a vaccine based on the M recombinant antigen of Histoplasma capsulatum. The third subproject aims to establish new alternative experimental models of PCM (using the lepidoptera Galleria Mellonela), and develop studies on the PCM pathogenicity in this model. The 4th subproject will address the influence of the P10 in the biofilm formation in Paracoccidioides spp. Biofilm formation represents one of the major issues in the therapy of invasive fungal infections as this fungi colony structure is able to promote antifungal resistance. Finally, the last approach will focus the role of tobacco exposure as a determinant factor in development of the chronic, pulmonary form of the disease, since virtually 100% of the patients presenting this form have a history of tobacco smoking. Overall, we expect to provide significant advances in the design of a vaccine strategy not only against human PCM, but also against histoplasmosis, in parallel to strengthen our understanding of the immunpathogenesis of these two systemic mycoses that still represent public health challenges in Brazil. (AU)
Articles published in Agência FAPESP Newsletter about the research grant:
ALVES DE PAULA E SILVA, ANA CAROLINA;
DE OLIVEIRA, HAROLDO CESAR;
DOS SANTOS, CLAUDIA TAVARES;
SINGULANI, JUNYA DE LACORTE;
ASSATO, PATRICIA AKEMI;
MARCOS, CAROLINE MARIA;
OLIVEIRA, LARIANE TEODORO;
FREGONEZI, NATHALIA FERREIRA;
PEREIRA ROSSI, DIEGO CONRADO;
ROQUE DA SILVA, LEANDRO BUFFONI;
TABORDA, CARLOS PELLESCHI;
FUSCO-ALMEIDA, ANA MARISA;
SOARES MENDES-GIANNINI, MARIA JOSE.
In Vitro and In Vivo Effect of Peptides Derived from 14-3-3 Paracoccidioides spp. Protein.
JOURNAL OF FUNGI,
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