Cigarette Smoke Decreases Innate Responses of Epithelial Cells to Rhinovirus Infection

Abstract

Exposure to cigarette smoke is associated with a significant increase in the risk for respiratory viral infections. The airway epithelium is the primary target for both cigarette smoke and respiratory viral infection. We investigated the effects of cigarette smoke on the response of airway epithelial cells to rhinovirus infection. We found that pre-exposure of BEAS-2B cells or primary normal human bronchial epithelial cells (NHBEs) to cigarette smoke extract (CSE) reduced the induction of mRNA of the chemokines CXCL10 and CCL5 by either the viral mimic polyinosine-polycytidylic acid (Poly I:C) or human rhinovirus 16 (HRV-16) infection. The HRV-16-induced release of CXCL10 and CCL5 was also significantly suppressed by CSE. Activation of the IFN mediator STAT-1 and the activation of JNK by poly I:C and HRV-16 were partially suppressed by pre-exposure to CSE. In contrast, the poly I:C-induced and HRV-16-induced phosphorylation of ERK1/2 was unaffected by CSE. HRV-16-stimulated IFN-b mRNA was also significantly reduced by CSE. Because suppression of the IFN response to viral infection was associated with increased viral production, we assessed HRV-16 RNA concentrations. Exposure to CSE resulted in an increase in HRV-16 RNA at 48 hours after the infection of BEAS-2B cells. These data demonstrate that exposure to CSE alters the response of airway epithelial cells to HRV infection, leading to decreased activation of the IFN-STAT-1 and SAP-JNK pathways, the suppression of CXCL10 and CCL5 production, and increased viral RNA. A diminished, early epithelial-initiated antiviral response to rhinovirus infection could contribute to the increased susceptibility of subjects to prolonged respiratory viral infections after exposure to cigarette smoke.

Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature

“…Third, RV strains have evolved to evade IFN responses (8). Finally, diminished IFN responses in the airway epithelium are associated with conditions such as asthma and cigarette smoke exposure, in which RV infection results in exacerbated disease (22)(23)(24). Although diverse lines of evidence suggest that virus-induced IFNs contribute to defense against RV infection, increasing evidence from studies in bronchial epithelial cells indicates that the mechanisms involved (i.e., the RLR signaling pathway) require time for up-regulation before mediating a robust IFN response (6,7,9).…”

Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers

“…Although elevated STAT1 has not been reported in NECs from smokers, STAT1 levels are correlated with COPD diagnosis, and downstream STAT1-dependent genes such as NOS2 are induced in smokers (4,10). Additionally, studies performed in bronchial epithelial cell lines have shown that pretreatment with cigarette smoke extract (CSE) reduces STAT1 activation, whereas other studies report that CSE treatment increased STAT1 activation (13,37).…”

Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease

“…TLRs play an important role in defense and it can thus be hypothesized that poor TLR function contribute greatly to pulmonary disease exacerbation. Reduced TLR function could cause disease worsening because of comprised sensing of bacterial or viral components (Laan et al, 2004;Kulkarni et al, 2010;Eddleston et al, 2011;Manzel et al, 2011) as well as a reduced ability to phagocytose bacteria (Hodge et al, 2007b;Phipps et al, 2010) and apoptotic cells (Hodge et al, 2003;Richens et al, 2009 …”