Abstract
Human rhinovirus (HRV) infections trigger acute exacerbations of chronic obstructive pulmonary disease (COPD) and asthma. The human airway epithelial cell is the primary site of HRV infection and responds to infection with altered expression of multiple genes, the products of which could regulate the outcome to infection. Cigarette smoking aggravates asthma symptoms, and is also the predominant risk factor for the development and progression of COPD. We, therefore, examined whether cigarette smoke extract (CSE) modulates viral responses by altering HRV-induced epithelial gene expression. Primary cultures of human bronchial epithelial cells were exposed to medium alone, CSE alone, purified HRV-16 alone or to HRV-16+ CSE. After 24 h, supernatants were collected and total cellular RNA was isolated. Gene array analysis was performed to examine mRNA expression. Additional experiments, using real-time RT-PCR, ELISA and/or western blotting, validated altered expression of selected gene products. CSE and HRV-16 each induced groups of genes that were largely independent of each other. When compared to gene expression in response to CSE alone, cells treated with HRV+CSE showed no obvious differences in CSE-induced gene expression. By contrast, compared to gene induction in response to HRV-16 alone, cells exposed to HRV+CSE showed marked suppression of expression of a number of HRV-induced genes associated with various functions, including antiviral defenses, inflammation, viral signaling and airway remodeling. These changes were not associated with altered expression of type I or type III interferons. Thus, CSE alters epithelial responses to HRV infection in a manner that may negatively impact antiviral and host defense outcomes.
Highlights
Human rhinoviruses are the predominant cause of the common cold, but are the major viral pathogens associated with acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) [1,2]
human rhinovirus (HRV)-induced release of IFNb from primary epithelial cell cultures could not be detected in any experiment using an ELISA with a minimum detection limit of 2.5 pg/ml. This was not due to degradation of protein as recovery of 50 pg/ml of recombinant IFNb added to samples was 92.462.6%. The goal of these studies was to determine if cigarette smoke extract (CSE) altered epithelial responses to HRV infection in a manner that, if reproduced by cigarette smoking in vivo, may be expected to lead to worse clinical outcomes to infection
We showed that both CSE and HRV-16 alter epithelial gene expression, but that the patterns of genes affected by each stimulus were quite discrete with no obvious overlap
Summary
Human rhinoviruses are the predominant cause of the common cold, but are the major viral pathogens associated with acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) [1,2]. In both the upper and lower airways, the primary site of human rhinovirus (HRV) infection is the airway epithelial cell [3,4]. Cigarette smokers experience more frequent and severe upper respiratory viral infections than nonsmokers [9,10]. Subjects hospitalized for rhinovirus-induced exacerbations of asthma were significantly more likely to be current smokers [12]
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