Modulation of airway epithelial antiviral immunity by fungal exposure
Lingxiang Zhu1, Boram Lee, Fangkun Zhao
11 Department of Pharmacology and Toxicology, School of Pharmacy, University of Arizona, Tucson, Arizona; and.
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.
Insights
Alternaria alternata fungus worsens asthma by increasing inflammation and decreasing antiviral responses during viral infections. This fungus impacts airway immunity, leading to more severe respiratory symptoms.
Area of Science:
- Immunology
- Respiratory Medicine
- Mycology
Background:
- Airway pathogens like fungi and viruses are linked to asthma exacerbation.
- Alternaria alternata (Alt) and human rhinovirus are common in asthma, but their interaction is unknown.
Purpose of the Study:
- To investigate the impact of Alt on virus-induced airway epithelial immune responses.
- To elucidate the mechanisms behind Alt's effects on cytokine and interferon production.
Main Methods:
- Exposure of airway epithelial cells to live virus or double-stranded RNA (dsRNA) with or without Alt.
- Measurement of proinflammatory cytokines (IL-6, IL-8) and type I/III interferons (IFNs).
- Analysis of signaling pathways including NF-κB, MAPK, TBK1-IRF3.
Main Results:
- Alt synergistically enhanced virus-induced IL-6 and IL-8 production.
- Alt significantly repressed type I and III IFN production, increasing viral replication.
- Mechanisms involved NF-κB and MAPK activation for inflammation, and TBK1-IRF3 attenuation for IFN suppression.
Conclusions:
- Alternaria alternata shifts airway epithelial immunity towards increased inflammation and reduced antiviral defense during viral infections.
- Separate fungal components mediate the opposing effects on inflammatory and antiviral pathways.
- Understanding these interactions is crucial for managing asthma exacerbations triggered by fungal and viral co-infections.
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