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Design of new therapeutic strategies, based on the carbohydrate recognition, against cryptococcosis

Grant number: 16/04877-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2016
Effective date (End): October 31, 2019
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal researcher:Maria Cristina Roque Antunes Barreira
Grantee:Thiago Aparecido da Silva
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):16/23044-1 - Engineered T cells expressing carbohydrate recognition domain of ArtinM lectin to activate macrophages and treat cryptococcosis, BE.EP.PD

Abstract

Cryptococcus gattii is found in tropical climatic zones, subtropical and temperate; cause cryptococcosis in immunocompetent host, including children. C. gattii infection is caused by the inhalation of spores and yeast. This pathogen has a predilection for the lung, and can spread to CNS. The pathogenesis of the cryptococcosis is influenced by virulence factors, mainly the polysaccharide capsule. C. gattii capacity to subvert the response of innate immunity reduces the microbicidal activity of phagocytes and impairs the Th1 and Th17 immune response, which act in effector response against cryptococcosis. Antifungal drugs are used as treatment and was reported the toxicity activity and limited to eliminate the C. gattii infection. Immunotherapy was proposed as an alternative form to subvert the regulation the immune response by C. gattii. Immunomodulatory agents induce an appropriate immune response, which the innate immunity receptors are potential mediators. This immumomodulatory effect could be promoted by lectins that interact with N-glycans of Toll-like receptors (TLRs) and trigger activation. Our group described this mechanism for lectins, which induce the Th1 and Th17 immune response that protects against P. brasiliensis and Candida albicans infection. This evidence support the lectins ability to modulate the immune response in fungal infections, which is a therapeutic strategies to treat the cryptococcosis. Therefore, we propose as therapeutic strategie against C. gattii infection based on the lectins recognition by N-glycans linked to receptors of immune cells. So, ArtinM, Paracoccin, ConA, L-PHA and WGA, which will be used to assay the immunomodulatory effect in vitro and in vivo models infections. After, the following parameters will be analyzed: phagocytic activity and killing of innate immune cells; levels of cytokines and chemokines; measurement of reactive oxygen and nitrogen species; expression of costimulatory molecules; relative expression of markers of polarization of macrophages and CD4+ T cells; molecules phosphorylated of the TLR signaling pathway, expression levels of virulence factors of C. gattii; GXM levels; histopathology; cellular profile of inflammatory infiltrate; fungal burden in organs; survival curve. To innovate, T cells will be modified to express the chimeric antigenic receptor (CAR) containing the CRDs, fact that allows the interaction with glycotargets promoting the activation of innate and adaptive immune cells. This proposal will be evaluate in vitro after infection with C. gattii, in the presence of macrophages and genetically modified T cells. After, the following parameters will be analyzed: fungal burden in immune cells, levels of cytokines and chemokines, production of reactive oxygen and nitrogen species, release of perforin and granzyme, expression levels of virulence factors of C. gattii. These results to open new perspectives and to support the application in vivo models infection with C. gattii.

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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)
SILVA, THIAGO APARECIDO DA; HAUSER, PAUL J.; BANDEY, IRFAN; LASKOWSKI, TAMARA; WANG, QI; NAJJAR, AMER M.; KUMARESAN, PAPPANAICKEN R. Glucuronoxylomannan in the Cryptococcus species capsule as a target for Chimeric Antigen Receptor T-cell therapy. CYTOTHERAPY, v. 23, n. 2, p. 119-130, FEB 2021. Web of Science Citations: 0.
MARTINS OLIVEIRA-BRITO, PATRICIA KELLEN; REZENDE, CAROLINE PATINI; ALMEIDA, FAUSTO; ROQUE-BARREIRA, MARIA CRISTINA; DA SILVA, THIAGO APARECIDO. iNOS/Arginase-1 expression in the pulmonary tissue over time during Cryptococcus gattii infection. Innate Immunity, v. 26, n. 2 AUG 2019. Web of Science Citations: 0.
MARTINS OLIVEIRA-BRITO, PATRICIA KELLEN; ROQUE-BARREIRA, MARIA CRISTINA; DA SILVA, THIAGO APARECIDO. The Response of IL-17-Producing B Cells to ArtinM Is Independent of Its Interaction with TLR2 and CD14. Molecules, v. 23, n. 9 SEP 2018. Web of Science Citations: 0.
MARTINS OLIVEIRA BRITO, PATRICIA KELLEN; GONCALVES, THIAGO ELEUTERIO; FERNANDES, FABRICIO FREITAS; MIGUEL, CAMILA BOTELHO; RODRIGUES, WELLINGTON FRANCISCO; LAZO CHICA, JAVIER EMILIO; ROQUE-BARREIRA, MARIA CRISTINA; DA SILVA, THIAGO APARECIDO. Systemic effects in naive mice injected with immunomodulatory lectin ArtinM. PLoS One, v. 12, n. 10 OCT 30 2017. Web of Science Citations: 4.
DA SILVA, THIAGO APARECIDO; ZORZETTO-FERNANDES, ANDRE L. V.; CECILIO, NERRY T.; SARDINHA-SILVA, ALINE; FERNANDES, FABRICIO FREITAS; ROQUE-BARREIRA, MARIA CRISTINA. CD14 is critical for TLR2-mediated M1 macrophage activation triggered by N-glycan recognition. SCIENTIFIC REPORTS, v. 7, AUG 1 2017. Web of Science Citations: 12.
DA SILVA, THIAGO APARECIDO; MARTINS OLIVEIRA-BRITO, PATRICIA KELLEN; GONCALVES, THIAGO ELEUTERIO; VENDRUSCOLO, PATRICIA EDIVANIA; ROQUE-BARREIRA, MARIA CRISTINA. ArtinM Mediates Murine T Cell Activation and Induces Cell Death in Jurkat Human Leukemic T Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 18, n. 7 JUL 2017. Web of Science Citations: 5.
FERNANDES, FABRICIO F.; OLIVEIRA, ALINE F.; LANDGRAF, TAISE N.; CUNHA, CRISTINA; CARVALHO, AGOSTINHO; VENDRUSCOLO, PATRICIA E.; GONCALES, RELBER A.; ALMEIDA, FAUSTO; DA SILVA, THIAGO A.; RODRIGUES, FERNANDO; ROQUE-BARREIRA, MARIA CRISTINA. Impact of Paracoccin Gene Silencing on Paracoccidioides brasiliensis Virulence. MBIO, v. 8, n. 4 JUL-AUG 2017. Web of Science Citations: 5.
DA SILVA, THIAGO APARECIDO; ROQUE-BARREIRA, MARIA CRISTINA; CASADEVALL, ARTURO; ALMEIDA, FAUSTO. Extracellular vesicles from Paracoccidioides brasiliensis induced M1 polarization in vitro. SCIENTIFIC REPORTS, v. 6, OCT 24 2016. Web of Science Citations: 14.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.