title: Modulation of airway epithelial antiviral immunity by fungal exposure.
abstract: Multiple pathogens, such as bacteria, fungi, and viruses, have been frequently found in asthmatic airways and are associated with the pathogenesis and exacerbation of asthma. Among these pathogens, Alternaria alternata (Alt), a universally present fungus, and human rhinovirus have been extensively studied. However, their interactions have not been investigated. In the present study, we tested the effect of Alt exposure on virus-induced airway epithelial immunity using live virus and a synthetic viral mimicker, double-stranded RNA (dsRNA). Alt treatment was found to significantly enhance the production of proinflammatory cytokines (e.g., IL-6 and IL-8) induced by virus infection or dsRNA treatment. In contrast to this synergistic effect, Alt significantly repressed type I and type III IFN production, and this impairment led to elevated viral replication. Mechanistic studies suggested the positive role of NF-κB and mitogen-activated protein kinase pathways in the synergism and the attenuation of the TBK1-IRF3 pathway in the inhibition of IFN production. These opposite effects are caused by separate fungal components. Protease-dependent and -independent mechanisms appear to be involved. Thus, Alt exposure alters the airway epithelial immunity to viral infection by shifting toward more inflammatory but less antiviral responses.
authors.affiliation: 1 Department of Pharmacology and Toxicology, School of Pharmacy, University of Arizona, Tucson, Arizona; and.
authors.forename: Lingxiang
authors.initials: L
authors.lastname: Zhu
authors.forename: Boram
authors.initials: B
authors.lastname: Lee
authors.forename: Fangkun
authors.initials: F
authors.lastname: Zhao
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.forename: Vanessa
authors.initials: V
authors.lastname: Chin
authors.forename: Serena C
authors.initials: SC
authors.lastname: Ling
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000528:Alternaria / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000821:virology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology; D012137:Respiratory System / Q000276:immunology* / Q000382:microbiology* / Q000821:virology; D012229:Rhinovirus / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D012367:RNA, Viral; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D020928:Mitogen-Activated Protein Kinases