Trehalose-Mediated Autophagy Impairs the Anti-Viral Function of Human Primary Airway Epithelial Cells

Qun Wu,Linda F Van Dyk,Chunjian Huang,Di Jiang,Hong Wei Chu,Liwu Li,Neeraj Vij

doi:10.1371/journal.pone.0124524

Qun Wu, Linda F Van Dyk + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0124524

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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.

Highlights

IntroductionHuman rhinovirus (HRV) is the most frequently detected respiratory virus in all age groups of human subjects who suffer from acute infections in the upper (e.g., common cold) as well as the lower (e.g., bronchiolitis and pneumonia) airways [1]
Human rhinovirus (HRV) is the most frequently detected respiratory virus in all age groups of human subjects who suffer from acute infections in the upper as well as the lower airways [1]
The 6 and 24 h time points post infection were chosen based on our preliminary time-course (6, 24 and 48 h) optimization experiments where cells were infected with HRV-16 at the dose of 104 TCID50/well

Summary

Introduction

Human rhinovirus (HRV) is the most frequently detected respiratory virus in all age groups of human subjects who suffer from acute infections in the upper (e.g., common cold) as well as the lower (e.g., bronchiolitis and pneumonia) airways [1]. Autophagy Promotes Human Rhinovirus Infection single stranded RNA, and has been categorized into major (e.g., HRV-16) and minor (e.g., HRV-1A and HRV-1B) groups that bind host cell intercellular adhesion molecule 1 and lowdensity lipoprotein receptor, respectively. Airway epithelial cells represent the primary site of HRV infection in vivo [4, 5]. Recent studies suggest that IFN-λ1, a type III antiviral interferon, is the major type of IFNs induced during HRV infection in human primary airway epithelial cells [6,7,8] and serves as a crucial anti-viral mechanism against HRV infection [9]. Impaired IFN-λ1 production and increased HRV-16 replication have been reported in cultured human airway epithelial cells from asthmatics [10]. The exact mechanisms underlying the impaired anti-viral interferon (i.e., IFN-λ1) response have not been well elucidated

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