Immunosuppression in paracoccidioidomycosis: the regulatory role of myeloid-derived suppressor cells (MDSCs) on host immunity, tissue pathology and genetic adaptation of fungal cells

• Grant number: 18/14762-3
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Duration: May 01, 2019 - April 30, 2024
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Flávio Vieira Loures
• Grantee: Flávio Vieira Loures
• Host Institution: Instituto de Ciência e Tecnologia (ICT). Universidade Federal de São Paulo (UNIFESP). Campus São José dos Campos. São José dos Campos , SP, Brazil
• Associated researchers: André Zelanis Palitot Pereira ; Claudia Barbosa Ladeira de Campos ; Gustavo Henrique Goldman ; Vera Lucia Garcia Calich
• Associated research grant: 14/04783-2 - Study of the plasmacytoid and myeloid dendritic cells function during Paracoccidioides brasiliensis infection, AP.JP
• Associated grant(s): 19/10097-8 - Multi-User Equipment approved in grant 2018/14762-3: flow cytometer FACS lyric, AP.EMU
• Associated scholarship(s): 23/14310-3 - Immunotherapy in Paracoccidioidomycosis: evaluation of combined therapy with antifungals and MDSCs depletion by 5-fluorouracil., BP.PD; 22/10654-7 - Immunomodulation of dendritic cells and cellular adaptive response promoted by extracellular vesicles obtained from P. brasiliensis yeasts extracted from chronic granulomatous lesions of C57BL/6 WT mice, BP.IC; 22/10707-3 - Action of Liver-X Receptor (LXR) agonists on the depletion of myeloid-derived suppressor cells (MDSCs) in the liver of mice infected with the fungus Paracoccidioides brasiliensis., BP.IC; + associated scholarships 21/09962-6 - Transcriptional and proteomic profile of Paracoccidiodes brasiliensis yeasts present in chronic granulomatous lesions of C57BL/6 WT mice, BP.DD; 19/24440-6 - The role of indoleamine 2, 3-dioxygenase 1 (IDO-1) in immunosuppressive mechanisms of myeloid-derived suppressor cells (MDSCs) in Pulmonary Paracoccidioidomycosis, BP.PD; 19/22285-3 - Action of Liver-X receptor (LXR) agonists on the depletion of myeloid derived supressor cells (MDSCs) in murine pulmonary paracoccidioidomycosis, BP.IC; 19/20892-0 - Bioinformatic analysis of transcriptional and proteomic profile of P. brasiliensis yeasts present in chronic granulomatous lesions of C57BL/6 WT mice, BP.TT; 19/17324-0 - Transcriptional and proteomic profile of Paracoccidiodes brasiliensis yeasts present in chronic granulomatous lesions of C57BL/6 WT mice, BP.MS; 19/09278-8 - The role of Myeloid-Derived Suppressor Cells (MDSCs) in Murine Paracoccidioidomycosis, BP.DD - associated scholarships

Abstract

Previous studies in paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America, revealed that immunity of hosts is tightly regulated by several suppressive mechanisms mediated by tolerogenic plasmacytoid dendritic cells, the enzyme 2,3 indoleamine dioxygenase (IDO1) and regulatory T cells (Treg). IDO1 was also seen to orchestrate local and systemic immunosuppressive effects through the recruitment and activation of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells with a potent ability to suppress T cell responses. These cells regulate immune responses and tissue repair in healthy individuals and rapidly expands during infection. The involvement of MDSC during PCM was never investigated, leading us to propose this study that aims to characterize the participation of MDSCs in the immunity against P. brasileinsis infection. The presence, phenotype and activity of MDSCs will be evaluated at several post infection periods. In addition, the disease severity and several features of the immune response will be assessed in MDSC-depleted and non-depleted C57BL/6 mice using a specific monoclonal antibody. Based on previous studies that established a positive correlation between IDO activity and MDCS infiltration we also intend to do a comparative study on MDSC function in pulmonary PCM using IDO-deficient and sufficient-mice. These studies will be complemented by the characterization of the transcriptional and proteomic responses of granulomatous lesions as well as P. brasiliensis yeasts obtained from these lesions at several post-infection periods. These data will be compared to those obtained from the original inoculum and non-infected lung tissue. This approach, never used in chronic PCM, will possibly reveal the main changes in gene expression and proteins production by P. brasiliensis cells under the stress conditions determined by the host immune system. A better understanding of immunoregulation in pulmonary PCM, mediated by MDSCs and adaptive behavior of yeasts cells in pulmonary granulomas will possibly advance the current knowledge of the host-pathogen responses that control the severity of PCM and will open new perspectives for more effective therapies. (AU)

Scientific publications

(5)

(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)

DE ARAUJO, ELISEU FRANK; PREITE, NYCOLAS WILLIAN; VELDHOEN, MARC; LOURES, FLAVIO VIEIRA; GARCIA CALICH, VERA LUCIA. Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses. SCIENTIFIC REPORTS, v. 10, n. 1, JUL 9 2020. (16/23189-0, 18/14762-3, 11/51258-2)

KAMINSKI, VALERIA DE LIMA; PREITE, NYCOLAS WILLIAN; BORGES, BRUNO MONTANARI; DOS SANTOS, BIANCA VIEIRA; CALICH, VERA LUCIA GARCIA; LOURES, FLAVIO VIEIRA. The immunosuppressive activity of myeloid-derived suppressor cells in murine Paracoccidioidomycosis relies on Indoleamine 2,3-dioxygenase activity and Dectin-1 and TLRs signaling. SCIENTIFIC REPORTS, v. 13, n. 1, p. 15-pg., 2023-07-18. (20/08460-4, 19/24440-6, 19/09278-8, 19/10097-8, 18/14762-3, 21/09962-6)

DE ARAUJO, ELISEU F.; LOURES, FLAVIO V.; PREITE, NYCOLAS W.; FERIOTTI, CLAUDIA; GALDINO, NAYANE A. L.; COSTA, TANIA A.; CALICH, VERA L. G.. AhR Ligands Modulate the Differentiation of Innate Lymphoid Cells and T Helper Cell Subsets That Control the Severity of a Pulmonary Fungal Infection. FRONTIERS IN IMMUNOLOGY, v. 12, APR 16 2021. (18/14762-3, 16/23189-0, 11/51258-2)

BASTOS, RAFAEL WESLEY; VALERO, CLARA; SILVA, LILIAN PEREIRA; SCHOEN, TAYLOR; DROTT, MILTON; BRAUER, VERONICA; SILVA-ROCHA, RAFAEL; LIND, ABIGAIL; STEENWYK, JACOB L.; ROKAS, ANTONIS; et al. Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen Aspergillus nidulans. MSPHERE, v. 5, n. 2, MAR-APR 2020. (19/00631-7, 18/14762-3, 16/07870-9, 17/14159-2, 17/19821-5)

PREITE, NYCOLAS WILLIAN; KAMINSKI, VALERIA DE LIMA; BORGES, BRUNO MONTANARI; CALICH, VERA LUCIA GARCIA; LOURES, FLAVIO VIEIRA. Myeloid-derived suppressor cells are associated with impaired Th1 and Th17 responses and severe pulmonary paracoccidioidomycosis which is reversed by anti-Gr1 therapy. FRONTIERS IN IMMUNOLOGY, v. 14, p. 19-pg., 2023-01-26. (18/14762-3, 19/24440-6, 21/09962-6, 19/09278-8)