1. Innate IFN-lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life.
- Author
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Salka K, Arroyo M, Chorvinsky E, Abutaleb K, Perez GF, Wolf S, Xuchen X, Weinstock J, Gutierrez MJ, Pérez-Losada M, Pillai DK, and Nino G
- Subjects
- Case-Control Studies, Cells, Cultured, Child, Preschool, Epithelial Cells metabolism, Epithelial Cells virology, Female, Host Microbial Interactions, Humans, Infant, Interferons metabolism, Male, NF-kappa B metabolism, Respiratory System metabolism, Respiratory System virology, Respiratory Tract Infections metabolism, Respiratory Tract Infections virology, Signal Transduction, Viral Load, Virus Diseases metabolism, Virus Diseases virology, p38 Mitogen-Activated Protein Kinases metabolism, Epithelial Cells immunology, Immunity, Innate, Interferons immunology, Poly I-C immunology, RNA, Double-Stranded immunology, Respiratory System immunology, Respiratory Tract Infections immunology, Virus Diseases immunology
- Abstract
Introduction: IFN lambda (type III-IFN-λ1) is a molecule primarily produced by epithelial cells that provides an important first-line defence against viral respiratory infections and has been linked to the pathogenesis of viral-induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN-lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections., Methods: IFN-lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN-lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters., Results: Our in vitro experiments showed that the poly(I:C)-induced innate production of IFN lambda in human infant AECs is regulated by (a) p38-MAPK/NF-kB dependent mechanism; and (b) exposure to pro-inflammatory signals such as IL1β. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus-induced IFN-lambda airway secretion; (b) subjects with RSV infection showed the highest IFN-lambda airway levels; and (c) individuals with the highest virus-induced IFN-lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8)., Conclusion: IFN-lambda responses to dsRNA in the human infant airway epithelium are regulated by p38-MAPK and NF-kB signalling. High in vivo IFN-lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children., (© 2020 John Wiley & Sons Ltd.)
- Published
- 2020
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