Anna Caretti1, Riccardo Torelli2, Federica Perdoni3, Monica Falleni4, Delfina Tosi4, Aida Zulueta1, Josefina Casas5, Maurizio Sanguinetti2, Riccardo Ghidoni1, Elisa Borghi3, Paola Signorelli6. 1. Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy. 2. Institute of Microbiology, Cattolica del Sacro Cuore University, Rome, Italy. 3. Microbiology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy. 4. Pathology Division, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy. 5. Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, IQAC-CSIC, Barcelona, Spain. 6. Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy. Electronic address: paola.signorelli@unimi.it.
Abstract
BACKGROUND: Fungal infections develop in pulmonary chronic inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). The available antifungal drugs may fail to eradicate fungal pathogens, that can invade the lungs and vessels and spread by systemic circulation taking advantage of defective lung immunity. An increased rate of sphingolipid de novo synthesis, leading to ceramide accumulation, was demonstrated in CF and COPD inflamed lungs. The inhibitor of sphingolipid synthesis myriocin reduces inflammation and ameliorates the response against bacterial airway infection in CF mice. Myriocin also inhibits sphingolipid synthesis in fungi and exerts a powerful fungistatic effect. METHODS: We treated Aspergillus fumigatus infected airway epithelial cells with myriocin and we administered myriocin-loaded nanocarriers to A. fumigatus infected mice lung. RESULTS: We demonstrate here that de novo synthesized ceramide mediates the inflammatory response induced by A. fumigatus infection in airway epithelia. CF epithelial cells are chronically inflamed and defective in killing internalized conidia. Myriocin treatment reduced ceramide increase and inflammatory mediator release whereas it upregulated HO1 and NOD2, allowing the recovery of a functional killing of conidia in these cells. Myriocin-loaded nanocarriers, intratracheally administered to mice, significantly reduced both the inflammatory response induced by A. fumigatus pulmonary challenge and fungal lung invasion. CONCLUSIONS: We conclude that inhibition of sphingolipid synthesis can be envisaged as a dual anti-inflammatory and anti-fungal therapy in patients suffering from chronic lung inflammation with compromised immunity. GENERAL SIGNIFICANCE: Myriocin represents a powerful agent for inflammatory diseases and fungal infection.
BACKGROUND:Fungal infections develop in pulmonary chronic inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). The available antifungal drugs may fail to eradicate fungal pathogens, that can invade the lungs and vessels and spread by systemic circulation taking advantage of defective lung immunity. An increased rate of sphingolipid de novo synthesis, leading to ceramide accumulation, was demonstrated in CF and COPD inflamed lungs. The inhibitor of sphingolipid synthesis myriocin reduces inflammation and ameliorates the response against bacterial airway infection in CF mice. Myriocin also inhibits sphingolipid synthesis in fungi and exerts a powerful fungistatic effect. METHODS: We treated Aspergillus fumigatus infected airway epithelial cells with myriocin and we administered myriocin-loaded nanocarriers to A. fumigatus infected mice lung. RESULTS: We demonstrate here that de novo synthesized ceramide mediates the inflammatory response induced by A. fumigatusinfection in airway epithelia. CF epithelial cells are chronically inflamed and defective in killing internalized conidia. Myriocin treatment reduced ceramide increase and inflammatory mediator release whereas it upregulated HO1 and NOD2, allowing the recovery of a functional killing of conidia in these cells. Myriocin-loaded nanocarriers, intratracheally administered to mice, significantly reduced both the inflammatory response induced by A. fumigatus pulmonary challenge and fungal lung invasion. CONCLUSIONS: We conclude that inhibition of sphingolipid synthesis can be envisaged as a dual anti-inflammatory and anti-fungal therapy in patients suffering from chronic lung inflammation with compromised immunity. GENERAL SIGNIFICANCE: Myriocin represents a powerful agent for inflammatory diseases and fungal infection.
Authors: Simone Bertini; Giuseppe Saccomanni; Sara Del Carlo; Maria Digiacomo; Claudia Gargini; Ilaria Piano; Giuseppe Matteo Campisi; Riccardo Ghidoni; Marco Macchia; Clementina Manera Journal: Molecules Date: 2017-07-17 Impact factor: 4.411
Authors: Fabiola Bonezzi; Marco Piccoli; Michele Dei Cas; Rita Paroni; Alessandra Mingione; Michelle M Monasky; Anna Caretti; Chiara Riganti; Riccardo Ghidoni; Carlo Pappone; Luigi Anastasia; Paola Signorelli Journal: Front Physiol Date: 2019-08-09 Impact factor: 4.566