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Fungal pathogenicity: environmental effects, immune response and vaccine modulation in the Brazilian endemic mycoses paracoccidioidomycosis and histoplasmosis

Grant number: 16/08730-6
Support type:Research Projects - Thematic Grants
Duration: December 01, 2016 - November 30, 2021
Field of knowledge:Biological Sciences - Microbiology - Applied Microbiology
Principal Investigator:Carlos Pelleschi Taborda
Grantee:Carlos Pelleschi Taborda
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Co-Principal Investigators:Gil Benard
Assoc. researchers:Ana Marisa Fusco Almeida ; Luiz Rodolpho Raja Gabaglia Travassos ; Maria José Soares Mendes Giannini ; Milton de Arruda Martins
Associated scholarship(s):18/26402-1 - Prospection of new epitopes with vaccine potential in the control of experimental infection by Histoplasma capsulatum, BP.DD
18/25171-6 - Prospection of new epitopes with vaccine potential in the control of experimental infection by Paracoccidioides lutzii, BP.PD
17/25780-0 - Presentation by human dendritic cells of peptides with vaccine capacity and prospection of pan-fungal antigens in paracoccidioidomycosis, BP.PD

Abstract

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)

Scientific publications (8)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BONICHE, CAMILA; ROSSI, SUELEN ANDREIA; KISCHKEL, BRENDA; BARBALHO, FILIPE VIEIRA; D'AUREA MOURA, AGATA NOGUEIRA; NOSANCHUK, JOSHUA D.; TRAVASSOS, LUIZ R.; TABORDA, CARLOS PELLESCHI. Immunotherapy against Systemic Fungal Infections Based on Monoclonal Antibodies. JOURNAL OF FUNGI, v. 6, n. 1 MAR 2020. Web of Science Citations: 0.
CAMILLA VIEIRA ESTEVES; ROSELI SANTOS DE FREITAS; WLADIMIR GUSHIKEN DE CAMPOS; NATALI SHIMABUKURO; DANILO YAMAMOTO THOMAZ; TAKI CORDAS; GIL BENARD; ANDREA LUSVARGHI WITZEL; CELSO AUGUSTO LEMOS. Oral yeast colonization in patients with eating disorders: commensal acquisition or due to purgative habits?. Revista do Instituto de Medicina Tropical de São Paulo, v. 62, p. -, 2020. Web of Science Citations: 0.
SILVA, LEANDRO B. R.; TAIRA, CLEISON L.; DIAS, LUCAS S.; SOUZA, ANA C. O.; NOSANCHUK, JOSHUA D.; TRAVASSOS, LUIZ R.; TABORDA, CARLOS P. Experimental Therapy of Paracoccidioidomycosis Using P10-Primed Monocyte-Derived Dendritic Cells Isolated From Infected Mice. FRONTIERS IN MICROBIOLOGY, v. 10, JUL 31 2019. Web of Science Citations: 0.
DUTRA DA SILVA XISTO, MARIANA INGRID; MUNOZ HENAO, JULIAN ESTEBAN; DIAS, LUCAS DOS SANTOS; PIRES SANTOS, GIULIA MARIA; ROCHA CALIXTOL, RENATA DE OLIVEIRA; BERNARDINO, MARIANA COLLODETTI; TABORDA, CARLOS PELLESCHI; BARRETO-BERGTER, ELIANA. Glucosylceramides From Lomentospora prolificans Induce a Differential Production of Cytokines and Increases the Microbicidal Activity of Macrophages. FRONTIERS IN MICROBIOLOGY, v. 10, MAR 22 2019. Web of Science Citations: 1.
TABORDA, C. P.; BUCCHERI, R.; BENARD, G.; DUARTE-NETO, A. N.; NOSANCHUK, J. D.; TRAVASSOS, L. R. Paracoccidioides spp. and Histoplasma capsulatum: Current and New Perspectives for Diagnosis and Treatment. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 18, n. 15, p. 1333-1348, 2018. Web of Science Citations: 1.
SILVA, LEANDRO B. R.; DIAS, LUCAS S.; RITTNER, GLAUCE M. G.; MUNOZ, JULIAN E.; SOUZA, ANA C. O.; NOSANCHUK, JOSHUA D.; TRAVASSOS, LUIZ R.; TABORDA, CARLOS P. Dendritic Cells Primed with Paracoccidioides brasiliensis Peptide P10 Are Therapeutic in Immunosuppressed Mice with Paracoccidioidomycosis. FRONTIERS IN MICROBIOLOGY, v. 8, JUN 14 2017. Web of Science Citations: 4.
VIEIRA, ANA PAULA; BIANCONCINI TRINDADE, MARIA ANGELA; DE PAULA, FLAVIO JOTA; SAKAI-VALENTE, NEUSA YURICO; DA SILVA DUARTE, ALBERTO JOSE; CARVALHINHO LEMOS, FRANCINE BRAMBATE; BENARD, GIL. Severe type 1 upgrading leprosy reaction in a renal transplant recipient: a paradoxical manifestation associated with deficiency of antigen-specific regulatory T-cells?. BMC INFECTIOUS DISEASES, v. 17, APR 24 2017. Web of Science Citations: 2.
TRAVASSOS, LUIZ R.; TABORDA, CARLOS P. Linear epitopes of Paracoccidioides brasiliensis and Other Fungal Agents of Human Systemic Mycoses As vaccine Candidates. FRONTIERS IN IMMUNOLOGY, v. 8, MAR 10 2017. Web of Science Citations: 5.

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