Abstract
Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients’ derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients’ monocytes killing of A. fumigatus. CF patients’ monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes.
Highlights
Cystic fibrosis (CF) is a hereditary disease associated with different classes of mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a chloride/carbonate channel.A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfoldedproteins accumulation, causing a proteinopathy responsible for inflammation, impaired autophagy, and altered lipid metabolism [1,2,3,4,5]
Regardless of the different origins of the cells, we found a common upregulation of HSP90AA1 and ZFAS1, two genes belonging to heat shock and zinc fingers proteins families, involved in chaperone-mediated autophagy
Our study demonstrates that the defective response to infection in CF is related to a dysfunction in autophagy, inflammation resolution, and lipid metabolism, which are known to be caused by mutated CFTR [1,2,3,4,5]
Summary
A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfoldedproteins accumulation, causing a proteinopathy responsible for inflammation, impaired autophagy, and altered lipid metabolism [1,2,3,4,5]. CF is a multiple-organ disease characterized by life-threatening chronic inflammation and recurrent infection of the lungs, where defective immune response and altered mucus viscosity and acidity pave the way to persistent microbial colonization [6]. CF is characterized by ineffective clearance of pathogens and reduced killing of internalized microbes, both in pulmonary airways epithelia and in macrophages [7,8,9]. Recurrent antibacterial therapies favor the insurgence of drug resistance and, by altering the microbiological milieu, promote colonization by opportunistic pathogens.
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