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-kB 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. Proteasedependent 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.

Role of Aspergillus fumigatus in Triggering Protease-Activated Receptor-2 in Airway Epithelial Cells and Skewing the Cells toward a T-helper 2 Bias

“…3A, B, and C), but activation of NF-κB was not affected. This observation is consistent with previous reports (28,29). Recently, we have reported a rapid dephosphorylation of IFN-β-induced phospho-STAT1 triggered by AF extract and have confirmed this in the present study (Supplemental Fig.…”

“…Previous studies by our laboratory and others have shown that extracts of Aspergillus fumigatus suppress Page 13 of 44 activation of epithelial cells by either IFN or by the TLR3 agonist poly I:C (6,18,28,29). In the present study, we show that AF extract also suppressed the HRV16-induced innate immune response in fully differentiated NHBE cells using an air liquid interface culture system (Fig.…”

Suppression of Epithelial Signal Transducer and Activator of Transcription 1 Activation by Extracts of Aspergillus fumigatus

“…The authors found that fungal proteases were involved in the induction of proinflamatory cytokines and were also responsible for the enhancement of virus-induced cytokine production by Alternaria. These authors also found that Alternaria suppresses virus-induced IFN-b production by a protease-independent mechanism (35). Our studies demonstrate an AF suppression of the response to IFN-b and may help to explain some of the findings of Zhu and colleagues (35).…”

“…These authors also found that Alternaria suppresses virus-induced IFN-b production by a protease-independent mechanism (35). Our studies demonstrate an AF suppression of the response to IFN-b and may help to explain some of the findings of Zhu and colleagues (35).…”

“…We used Aspergillus extract instead of hyphae and conidia in our study and found that IFN-b signaling plays an important role as a target in the mechanism of IP-10 suppression by Aspergillus extract. A recent study by Zhu and colleagues (35) explored the interaction between Alternaria and Rhinovirus, important pathogens in asthma. The authors found that fungal proteases were involved in the induction of proinflamatory cytokines and were also responsible for the enhancement of virus-induced cytokine production by Alternaria.…”