title: Sidestream smoke exposure increases the susceptibility of airway epithelia to adenoviral infection.
abstract: BACKGROUND
  Although significant epidemiological evidence indicates that cigarette smoke exposure increases the incidence and severity of viral infection, the molecular mechanisms behind the increased susceptibility of the respiratory tract to viral pathogens are unclear. Adenoviruses are non-enveloped DNA viruses and important causative agents of acute respiratory disease. The Coxsackievirus and adenovirus receptor (CAR) is the primary receptor for many adenoviruses. We hypothesized that cigarette smoke exposure increases epithelial susceptibility to adenovirus infection by increasing the abundance of apical CAR.
  
  
  RESULTS
  Cultured human airway epithelial cells (CaLu-3) were used as a model to investigate the effect of sidestream cigarette smoke (SSS), mainstream cigarette smoke (MSS), or control air exposure on the susceptibility of polarized respiratory epithelia to adenoviral infection. Using a Cultex air-liquid interface exposure system, we have discovered novel differences in epithelial susceptibility between SSS and MSS exposures. SSS exposure upregulates an eight-exon isoform of CAR and increases adenoviral entry from the apical surface whilst MSS exposure is similar to control air exposure. Additionally, the level of cellular glycogen synthase kinase 3β (GSK3β) is downregulated by SSS exposure and treatment with a specific GSK3β inhibitor recapitulates the effects of SSS exposure on CAR expression and viral infection.
  
  
  CONCLUSIONS
  This is the first time that SSS exposure has been shown to directly enhance the susceptibility of a polarized epithelium to infection by a common respiratory viral pathogen. This work provides a novel understanding of the impact of SSS on the burden of respiratory viral infections and may lead to new strategies to alter viral infections. Moreover, since GSK3β inhibitors are under intense clinical investigation as therapeutics for a diverse range of diseases, studies such as these might provide insight to extend the use of clinically relevant therapeutics and increase the understanding of potential side effects.
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, Ohio, United States of America.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Sharma
authors.forename: Abimbola O
authors.initials: AO
authors.lastname: Kolawole
authors.forename: Susan B
authors.initials: SB
authors.lastname: Core
authors.forename: Adriana E
authors.initials: AE
authors.lastname: Kajon
authors.forename: Katherine J D A
authors.initials: KJ
authors.lastname: Excoffon
mesh_terms: D000257:Adenoviridae Infections / Q000209:etiology / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004198:Disease Susceptibility / Q000821:virology*; D017097:Electric Impedance; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D017931:DNA Primers; D014028:Tobacco Smoke Pollution; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3