Reduced expression of IRF7 in nasal epithelial cells from smokers after infection with influenza.
Smokers are more susceptible to respiratory viral infections, including influenza virus, but the mechanisms mediating this effect are unknown. To determine how epithelial cells contribute to the enhanced susceptibility seen in smokers, we established an in vitro model of differentiated nasal epithelial cells (NECs) from smokers, which showed enhanced mucin expression. The NECs from smokers responded to influenza infection with greater cytotoxicity, release of interleukin-6, and viral shedding than NECs from nonsmokers. Focusing on type I interferon (IFN) expression, we observed that influenza-infected NECs from smokers produced significantly less IFN-alpha than NECs from nonsmokers. Similarly, the expression of IRF7, a key transcription factor controlling the expression of IFN-alpha, was significantly decreased in influenza-infected and IFN-beta-stimulated NECs from smokers. Furthermore, our data indicate that the DNA methylation of the IRF7 gene and expression of the DNA (cytosine-5-)-methyltransferase 1 was enhanced in NECs from smokers. To confirm these findings in vivo, we initiated a study in which smoking and nonsmoking healthy volunteers were inoculated nasally with the live-attenuated influenza virus (LAIV) vaccine, and nasal biopsies were obtained before and after the administration of LAIV. The LAIV-induced expression of IRF7 was lower in the nasal epithelium from smokers, supporting our in vitro observations. These data demonstrate that infection with influenza results in the reduced expression of transcription factor IRF7 in NECs from smokers, and that these effects may be mediated by an epigenetic modification of the IRF7 gene, thus providing a potential mechanism rendering smokers more susceptible to respiratory virus infections.
Jaspers
Ilona
I
Department of Pediatrics, University of North Carolina at Chapel Hill, 27599, USA. Ilona_jaspers@med.unc.edu
Horvath
Katherine M
KM
Zhang
Wenli
W
Brighton
Luisa E
LE
Carson
Johnny L
JL
Noah
Terry L
TL
D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D007124:Immunoenzyme Techniques; D053122:Influenza A Virus, H3N2 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000378:metabolism* / Q000821:virology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009297:Nasal Mucosa / Q000378:metabolism* / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000378:metabolism*; D055815:Young Adult
D016207:Cytokines; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D007770:L-Lactate Dehydrogenase