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Trehalose-mediated autophagy impairs the anti-viral function of human primary airway epithelial cells.

Wu Q, Jiang D, Huang C, van Dyk LF, Li L, Chu HW - PLoS ONE (2015)

Bottom Line: We found that trehalose-induced autophagy significantly impaired IFN-λ1 expression and increased HRV-16 load.Inhibition of autophagy via knockdown of autophagy-related gene 5 (ATG5) effectively rescued the impaired IFN-λ1 expression by trehalose and subsequently reduced HRV-16 load.Intervention of excessive autophagy in chronic lung diseases may provide a novel approach to attenuate viral infections and associated disease exacerbations.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.

ABSTRACT
Human rhinovirus (HRV) is the most common cause of acute exacerbations of chronic lung diseases including asthma. Impaired anti-viral IFN-λ1 production and increased HRV replication in human asthmatic airway epithelial cells may be one of the underlying mechanisms leading to asthma exacerbations. Increased autophagy has been shown in asthmatic airway epithelium, but the role of autophagy in anti-HRV response remains uncertain. Trehalose, a natural glucose disaccharide, has been recognized as an effective autophagy inducer in mammalian cells. In the current study, we used trehalose to induce autophagy in normal human primary airway epithelial cells in order to determine if autophagy directly regulates the anti-viral response against HRV. We found that trehalose-induced autophagy significantly impaired IFN-λ1 expression and increased HRV-16 load. Inhibition of autophagy via knockdown of autophagy-related gene 5 (ATG5) effectively rescued the impaired IFN-λ1 expression by trehalose and subsequently reduced HRV-16 load. Mechanistically, ATG5 protein interacted with retinoic acid-inducible gene I (RIG-I) and IFN-β promoter stimulator 1 (IPS-1), two critical molecules involved in the expression of anti-viral interferons. Our results suggest that induction of autophagy in human primary airway epithelial cells inhibits the anti-viral IFN-λ1 expression and facilitates HRV infection. Intervention of excessive autophagy in chronic lung diseases may provide a novel approach to attenuate viral infections and associated disease exacerbations.

No MeSH data available.


Related in: MedlinePlus

Inhibition of autophagy rescues the impaired IFN-λ1 expression by trehalose and subsequently reduces HRV-16 load in normal human primary airway epithelial cells.Normal human tracheobronchial epithelial cells were transfected with Naito1 chimera RNAi (control siRNA) or ATG5 chimera siRNA (ATG5 siRNA). Twenty-four hours after siRNA transfection, cells were treated with medium or trehalose (TRE, 100 mM) for 48 h and then infected with HRV-16 (104 TCID50/well) for 2 h. After removing the free viruses, cells were incubated with medium or trehalose for additional 6 h. The expression of IFN-λ1 mRNA (A) and viral RNA levels (B) were quantified by quantitative real-time RT-PCR. Data are presented as mean ± SEM (n = 2 independent experiments with each being performed in triplicate wells). NS, not significant; *, p<0.05.
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pone.0124524.g005: Inhibition of autophagy rescues the impaired IFN-λ1 expression by trehalose and subsequently reduces HRV-16 load in normal human primary airway epithelial cells.Normal human tracheobronchial epithelial cells were transfected with Naito1 chimera RNAi (control siRNA) or ATG5 chimera siRNA (ATG5 siRNA). Twenty-four hours after siRNA transfection, cells were treated with medium or trehalose (TRE, 100 mM) for 48 h and then infected with HRV-16 (104 TCID50/well) for 2 h. After removing the free viruses, cells were incubated with medium or trehalose for additional 6 h. The expression of IFN-λ1 mRNA (A) and viral RNA levels (B) were quantified by quantitative real-time RT-PCR. Data are presented as mean ± SEM (n = 2 independent experiments with each being performed in triplicate wells). NS, not significant; *, p<0.05.

Mentions: In keeping with above data, trehalose treatment significantly inhibited HRV-induced IFN-λ1 mRNA expression in both control siRNA- and ATG5 siRNA-treated cells (Fig 5A). Importantly, HRV-induced IFN-λ1 mRNA levels were significantly higher in ATG5 siRNA-treated cells vs. control siRNA-treated cells. Lastly, ATG5 knockdown prevented the increase of intracellular HRV-16 RNA levels after trehalose treatment (Fig 5B).


Trehalose-mediated autophagy impairs the anti-viral function of human primary airway epithelial cells.

Wu Q, Jiang D, Huang C, van Dyk LF, Li L, Chu HW - PLoS ONE (2015)

Inhibition of autophagy rescues the impaired IFN-λ1 expression by trehalose and subsequently reduces HRV-16 load in normal human primary airway epithelial cells.Normal human tracheobronchial epithelial cells were transfected with Naito1 chimera RNAi (control siRNA) or ATG5 chimera siRNA (ATG5 siRNA). Twenty-four hours after siRNA transfection, cells were treated with medium or trehalose (TRE, 100 mM) for 48 h and then infected with HRV-16 (104 TCID50/well) for 2 h. After removing the free viruses, cells were incubated with medium or trehalose for additional 6 h. The expression of IFN-λ1 mRNA (A) and viral RNA levels (B) were quantified by quantitative real-time RT-PCR. Data are presented as mean ± SEM (n = 2 independent experiments with each being performed in triplicate wells). NS, not significant; *, p<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400043&req=5

pone.0124524.g005: Inhibition of autophagy rescues the impaired IFN-λ1 expression by trehalose and subsequently reduces HRV-16 load in normal human primary airway epithelial cells.Normal human tracheobronchial epithelial cells were transfected with Naito1 chimera RNAi (control siRNA) or ATG5 chimera siRNA (ATG5 siRNA). Twenty-four hours after siRNA transfection, cells were treated with medium or trehalose (TRE, 100 mM) for 48 h and then infected with HRV-16 (104 TCID50/well) for 2 h. After removing the free viruses, cells were incubated with medium or trehalose for additional 6 h. The expression of IFN-λ1 mRNA (A) and viral RNA levels (B) were quantified by quantitative real-time RT-PCR. Data are presented as mean ± SEM (n = 2 independent experiments with each being performed in triplicate wells). NS, not significant; *, p<0.05.
Mentions: In keeping with above data, trehalose treatment significantly inhibited HRV-induced IFN-λ1 mRNA expression in both control siRNA- and ATG5 siRNA-treated cells (Fig 5A). Importantly, HRV-induced IFN-λ1 mRNA levels were significantly higher in ATG5 siRNA-treated cells vs. control siRNA-treated cells. Lastly, ATG5 knockdown prevented the increase of intracellular HRV-16 RNA levels after trehalose treatment (Fig 5B).

Bottom Line: We found that trehalose-induced autophagy significantly impaired IFN-λ1 expression and increased HRV-16 load.Inhibition of autophagy via knockdown of autophagy-related gene 5 (ATG5) effectively rescued the impaired IFN-λ1 expression by trehalose and subsequently reduced HRV-16 load.Intervention of excessive autophagy in chronic lung diseases may provide a novel approach to attenuate viral infections and associated disease exacerbations.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.

ABSTRACT
Human rhinovirus (HRV) is the most common cause of acute exacerbations of chronic lung diseases including asthma. Impaired anti-viral IFN-λ1 production and increased HRV replication in human asthmatic airway epithelial cells may be one of the underlying mechanisms leading to asthma exacerbations. Increased autophagy has been shown in asthmatic airway epithelium, but the role of autophagy in anti-HRV response remains uncertain. Trehalose, a natural glucose disaccharide, has been recognized as an effective autophagy inducer in mammalian cells. In the current study, we used trehalose to induce autophagy in normal human primary airway epithelial cells in order to determine if autophagy directly regulates the anti-viral response against HRV. We found that trehalose-induced autophagy significantly impaired IFN-λ1 expression and increased HRV-16 load. Inhibition of autophagy via knockdown of autophagy-related gene 5 (ATG5) effectively rescued the impaired IFN-λ1 expression by trehalose and subsequently reduced HRV-16 load. Mechanistically, ATG5 protein interacted with retinoic acid-inducible gene I (RIG-I) and IFN-β promoter stimulator 1 (IPS-1), two critical molecules involved in the expression of anti-viral interferons. Our results suggest that induction of autophagy in human primary airway epithelial cells inhibits the anti-viral IFN-λ1 expression and facilitates HRV infection. Intervention of excessive autophagy in chronic lung diseases may provide a novel approach to attenuate viral infections and associated disease exacerbations.

No MeSH data available.


Related in: MedlinePlus