IL-22 Promotes IFN-γ-Mediated Immunity against Histoplasma capsulatum Infection.

Morgana K.B Prado,Luiz G Gardinassi,José C Alves-Filho,Carlos A Sorgi,Ana P.F Peti,Karina F Zoccal,Alyne F.G Meirelles,Lúcia H Faccioli,Simone G Ramos,Camila O.S Souza,Francisco W.G De Paula-Silva,Caroline Fontanari

doi:10.3390/biom10060865

Morgana K.B Prado, Luiz G Gardinassi + Show 10 more

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https://doi.org/10.3390/biom10060865

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Abstract

Histoplasma capsulatum is the agent of histoplasmosis, one of the most frequent mycoses in the world. The infection initiates with fungal spore inhalation, transformation into yeasts in the lungs and establishment of a granulomatous disease, which is characterized by a Th1 response. The production of Th1 signature cytokines, such as IFN-γ, is crucial for yeast clearance from the lungs, and to prevent dissemination. Recently, it was demonstrated that IL-17, a Th17 signature cytokine, is also important for fungal control, particularly in the absence of Th1 response. IL-22 is another cytokine with multiple functions on host response and disease progression. However, little is known about the role of IL-22 during histoplasmosis. In this study, we demonstrated that absence of IL-22 affected the clearance of yeasts from the lungs and increased the spreading to the spleen. In addition, IL-22 deficient mice (Il22−/−) succumbed to infection, which correlated with reductions in the numbers of CD4+ IFN-γ+ T cells, reduced IFN-γ levels, and diminished nitric oxide synthase type 2 (NOS2) expression in the lungs. Importantly, treatment with rIFN-γ mitigated the susceptibility of Il22−/− mice to H. capsulatum infection. These data indicate that IL-22 is crucial for IFN-γ/NO production and resistance to experimental histoplasmosis.

Highlights

Histoplasma capsulatum is a dimorphic pathogenic fungus broadly distributed around the world, with high incidence in Asia, Africa and Americas [1,2]
To understand the role of IL-22 during experimental histoplasmosis, we monitored the mortality rate of C57Bl/6 (WT) or Il22−/− mice infected with H. capsulatum for 28 days
Considering that IFN-γ was reduced in the lungs of Il22−/− mice during H. capsulatum infection, we investigated the effect of IL-22 deficiency on transcriptional and protein expression of nitric oxide synthase type 2 (NOS2)

Summary

Introduction

Histoplasma capsulatum is a dimorphic pathogenic fungus broadly distributed around the world, with high incidence in Asia, Africa and Americas [1,2]. During the early stages of infection, pattern recognition receptors (PRRs) expressed by macrophages, dendritic cells (DCs) and neutrophils trigger intracellular signaling cascades that initiate antifungal responses such as phagocytosis, generation of reactive oxygen or nitrogen species (ROS or RNS), production of cytokines, chemokines and lipid mediators such as eicosanoids [7,8,9]. These bioactive lipids exhibit important functions during infections, including histoplasmosis [10,11,12,13]. Leukotriene B4 (LTB4), is required for effective phagocytosis of yeasts, production of ROS and RNS by macrophages, as well as for CD4+ T cell recruitment into the lungs of mice infected with H. capsulatum [12,14,15]

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