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

Eliseu Frank De Araújo,Flávio Vieira Loures,Nycolas Willian Preite,Marc Veldhoen,Vera Lúcia Garcia Calich

doi:10.1038/s41598-020-68322-6

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.

Highlights

AhR is a ligand-activated transcription factor that plays an important role in the innate and adaptive immune responses
The lack of AhR expression reduces cytokines, IDO-1 expression and Kyn synthesis by pulmonary DCs. This altered pulmonary microenvironment leads to defective innate immunity mechanisms with reduced participation of NK, innate lymphoid cells (ILCs)-3 and NCR-IL-22 cells
At the adaptive phase of immunity that subsequently develops, the lack of AhR leads to reduced expansion of the Th1, Th22 and Treg cells associated with increased Th17 development, whose pro-inflammatory activity is only partially controlled by the reduced number of Treg cells

Summary

Introduction

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. Two different AhR ligands (TCDD and FICZ) were shown to modulate the severity of experimental autoimmune encephalomyelitis in opposing directions[9,10] These findings led several investigators to study the role of AhR in diverse autoimmune, neoplastic and infectious diseases. In Candida albicans and Aspergillus fumigatus infections, the IDO enzyme was shown to concomitantly reduce fungal loads mediated by Trp starvation and inflammatory reactions due to the expansion of Treg cells via Kyn-induced AhR a ctivation[20,21,22]. The fungal propagules can be controlled by resident innate immune cell, can promote localized lesions, or can disseminate via hematogenous or lymphatic systems

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