Bromodomain inhibitor I‐BET151 suppresses immune responses during fungal–immune interaction

Jorge Domínguez‐Andrés,Mihai G Netea,Trees Jansen,Nicholas Smithers,Rebecca C Furze,Anaísa V Ferreira,Rab K Prinjha

doi:10.1002/eji.201848081

Abstract

Changes in the epigenetic landscape of immune cells are a crucial component of gene activation during the induction of inflammatory responses, therefore it has been hypothesized that epigenetic modulation could be employed to restore homeostasis in inflammatory scenarios. Fungal pathogens cause a large burden of morbidity and even mortality due to the hyperinflammatory processes that induce mucosal, allergic or systemic infections. Bromodomain and extraterminal domain (BET) proteins are considered as one as the most tantalizing pharmacological targets for the modulation of inflammatory responses at the epigenetic level. Nothing is known of the role of BET inhibitors on the inflammation induced by fungal pathogens. In the present study, we assessed the in vitro efficacy of the small molecular histone mimic BET inhibitor I‐BET151 to modulate innate immune responses during fungal–immune interaction with the clinically relevant fungal pathogens Candida albicans and Aspergillus fumigatus. Our results prove that BET inhibitors (I‐BETs) represent an important modulator of inflammation induced by fungal pathogens: both direct production of proinflammatory cytokines and the induction of trained immunity were inhibited by I‐BET151. These modulatory effects are likely to have important potential implications in clinically relevant situations.

Highlights

The incidence of fungal infections has risen dramatically over the past decade, with more than 2 million individuals suffering fromC 2019 The Authors
Immunity to infection 2045 design of effective therapies against fungal infections requires the development of new strategies that boost or optimize the actions of the host immune system, which could be combined with antifungal chemotherapy [1]
We studied the influence of two different concentrations (1 and 10 μM, representing IC50 and IC100 for inhibition of LPS-induced IL-6 production of human blood assays; Supporting Information Fig. 1) of I-BET151 in the cytokine production of whole blood (WB) cells after stimulation with heat-killed forms of the clinically relevant fungal pathogens Candida albicans and Aspergillus fumigatus (Fig. 1A)

Summary

Introduction

The incidence of fungal infections has risen dramatically over the past decade, with more than 2 million individuals suffering fromC 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Immunity to infection 2045 design of effective therapies against fungal infections requires the development of new strategies that boost or optimize the actions of the host immune system, which could be combined with antifungal chemotherapy [1]. One of the main mechanisms of pathogenicity during fungal infections is the development of excessive inflammation, due to the development of an exacerbated host immune innate response [4, 5]. New therapies that modulate inflammatory responses during fungal diseases can contribute to improve the outcome of these infections

Methods

Results

Conclusion