Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses

Author(s)

de Araujo, Eliseu Frank ^[1] ; Preite, Nycolas Willian ^{[2, 1]} ; Veldhoen, Marc ^[3] ; Loures, Flavio Vieira ^{[2, 1]} ; Garcia Calich, Vera Lucia ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, SP - Brazil

^[3] Fac Med Univ Lisboa, Inst Med Mol Joao Lobo Antunes, Lisbon - Portugal

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 10, n. 1 JUL 9 2020.
• Web of Science Citations: 3

Abstract

AhR is a ligand-activated transcription factor that plays an important role in the innate and adaptive immune responses. In infection models, it has been associated with host responses that promote or inhibit disease progression. In pulmonary paracoccidioidomycosis, a primary fungal infection endemic in Latin America, immune protection is mediated by Th1/Th17 cells and disease severity with predominant Th2/Th9/Treg responses. Because of its important role at epithelial barriers, we evaluate the role of AhR in the outcome of a pulmonary model of paracoccidioidomycosis. AhR(-/-) mice show increased fungal burdens, enhanced tissue pathology and mortality. During the infection, AhR(-/-) mice have more pulmonary myeloid cells with activated phenotype and reduced numbers expressing indoleamine 2,3 dioxygenase 1. AhR-deficient lungs have altered production of cytokines and reduced numbers of innate lymphoid cells (NK, ILC3 and NCR IL-22). The lungs of AhR(-/-) mice showed increased presence Th17 cells concomitant with reduced numbers of Th1, Th22 and Foxp3(+) Treg cells. Furthermore, treatment of infected WT mice with an AhR-specific antagonist (CH223191) reproduced the main findings obtained in AhR(-/-) mice. Collectively our data demonstrate that in pulmonary paracoccidioidomycosis AhR controls fungal burden and excessive tissue inflammation and is a possible target for antifungal therapy. (AU)

• FAPESP's process: 16/23189-0 - Modulation of Treg/Th17 responses by Aryl Hydrocarbon Receptor Ligands in the Search for an Immunotherapeutic Procedure for Pulmonary Paracoccidioidomycosis
• Grantee: Vera Lucia Garcia Calich
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/14762-3 - Immunosuppression in paracoccidioidomycosis: the regulatory role of myeloid-derived suppressor cells (MDSCs) on host immunity, tissue pathology and genetic adaptation of fungal cells
• Grantee: Flávio Vieira Loures
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 11/51258-2 - Influence of the enzyme indoleamine-2,3-dioxygenase (IDO) in the differentiation and function of dendritic cells and regulatory T cells in the pulmonary paracoccidioidomycosis of resistant and susceptible mice to P. brasiliensis infection
• Grantee: Vera Lucia Garcia Calich
• Support Opportunities: Regular Research Grants