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The importance of aryl hydrocarbon receptor (AhR) in the regulation of immune response and host resistance to pulmonary paracoccidioidomycosis

Grant number: 14/18668-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): November 01, 2014
Effective date (End): October 31, 2017
Field of knowledge:Biological Sciences - Immunology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Vera Lucia Garcia Calich
Grantee:Eliseu Frank de Araujo
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Paracoccidioidomycosis (PCM), a relevant systemic mycosis in Latin America, is caused by Paraccoccidioides brasiliensis (Pb). The innate immunity in PCM is poorly understood but our recent studies in the murine model of PCM have demonstrated the important role of indoleamine 2,3-dioxygenase (IDO), an enzyme that controls fungal burdens but also suppresses the innate and adaptive immune responses. IDO metabolizes the amino acid tryptophan in kynurenines that are recognized by the aryl hydrocarbon receptor (AhR), a cytoplasmatic nuclear factor that senses aromatic amines. AhR is expressed by a variety of cells, including dendritic cells (DCs), macrophages and lymphocytes of innate immunity. The activation of AhR by exogenous and endogenous agonists leads to diverse immune responses that may favor the development pro-inflammatory Th17 cells, or anti-inflammatory regulatory T cells (Treg) that negatively control inflammatory processes. Studies on the role of AhR in PCM are still lacking, justifying our proposal of evaluating the influence of this receptor in innate and adaptive phases of immunity developed by AhR genetically deficient mice (AhR-/-). Deficient and control mice C57BL/6 will be infected with 1 x 106 yeasts, and the immune responses will be evaluated in the early and late phases of infection. The inflammatory exudates, the activation and expression of transcription factors of T cell subsets, the phenotype of cell subpopulations that migrate to inflammatory sites and cytokines production will be comparatively evaluated in AhR-/- and wild type C57BL/6 mice. The severity of the disease will be also characterized by histopathology of organs and mortality rates. Moreover, genetically deficient mice for IDO, IL-17 and IL-22 will be sporadically used to characterize the importance of these mediators in the immunoprotection against pulmonary PCM, and their association with the regulatory function of AhR. Altogether, this proposal intends to obtain a comprehensive view on the importance of AhR in the immunity against pulmonary PCM, and improve our knowledge on the pathogenesis of this important systemic mycosis. Keywords: pulmonary paracoccidioidomycosis; innate and adaptive immunity; AhR; IDO; Treg; Th17; IL-22. (AU)

Scientific publications
(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)
GALDINO, NAYANE A. L.; LOURES, V, FLAVIO; DE ARAUJO, ELISEU F.; DA COSTA, TANIA A.; PREITE, NYCOLAS W.; CALICH, VERA LUCIA G. Depletion of regulatoryT cells in ongoing paracoccidioidomycosis rescues protective Thl/Th17 immunity and prevents fatal disease outcome. SCIENTIFIC REPORTS, v. 8, NOV 8 2018. Web of Science Citations: 1.
DE ARAUJO, ELISEU FRANK; LOURES, FLAVIO VIEIRA; FERIOTTI, CLAUDIA; COSTA, TANIA; VACCA, CARMINE; PUCCETTI, PAOLO; ROMANI, LUIGINA; GARCIA CALICH, VERA LUCIA. Disease Tolerance Mediated by Phosphorylated indoleamine-2,3 Dioxygenase confers resistance to a Primary Fungal Pathogen. FRONTIERS IN IMMUNOLOGY, v. 8, NOV 13 2017. Web of Science Citations: 2.
DE ARAUJO, ELISEU FRANK; MEDEIROS, DANIELLA HELENA; DE LIMA GALDINO, NAYANE ALVES; CONDINO-NETO, ANTONIO; GARCIA CALICH, VERA LUCIA; LOURES, FLAVIO VIEIRA. Tolerogenic Plasmacytoid Dendritic Cells Control Paracoccidioides brasiliensis Infection by Inducting Regulatory T Cells in an IDO-Dependent Manner. PLOS PATHOGENS, v. 12, n. 12 DEC 2016. Web of Science Citations: 10.

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