Reduced Expression of IRF7 in Nasal Epithelial Cells from Smokers after Infection with Influenza

Abstract

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-a than NECs from nonsmokers. Similarly, the expression of IRF7, a key transcription factor controlling the expression of IFN-a, was significantly decreased in influenza-infected and IFN-b-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 LAIVinduced 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.

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments

“…However, because of ethical considerations, there are limited clinical studies investigating the mechanisms involved; animal research (e.g., mouse, guinea pig, rat) has been proven advantageous in the exploration of the mechanisms involved in CSinduced COPD (15). In addition, recent studies (14,61,82) have demonstrated that CS can impair the antiviral host defense. For instance, type I IFN, a key mediator involved in antimicrobial signaling pathways, is attenuated after cigarette smoke exposure.…”

DNA methylation in nasal epithelial cells from smokers: identification of ULBP3-related effects

“…Smoking not only induces cellular damage and inflammation but also serves as an immunosuppressor (37). Although the underlying molecular mechanisms of smoking-induced disease remain largely unknown, one of the proposed mechanisms involves epigenetic modifications (e.g., DNA methylation) that potentially alter gene expression profiles of CS-exposed target cells (15,19,22,39). Genespecific epigenetic regulation can occur through loss or gain of cytosine methylation in promoter-associated cytosine-phosphate-guanine (CpG) islands (33).…”

“…For example, virus-induced cytokine and chemokine expression is modified in CS-exposed epithelial cells (30). We and others have previously demonstrated that CS exposure significantly alters interferon-dependent antiviral responses at the level of the epithelium (19,40). Exposure to CS also alters the ability of epithelial cells to communicate with resident immune cells, such as dendritic cells and Natural Killer (NK) cells in the context of viral infections (17,18).…”

The Tobacco Smoke Component, Acrolein, Suppresses Innate Macrophage Responses by Direct Alkylation of c-Jun N-Terminal Kinase

“…Transcriptional profiling of AMs in smokers has indicated a marked macrophage reprogramming in smokers (3,4), with suppression of inflammatory genes associated with classical M1-related inflammatory/immune genes and induction of genes associated with various M2-polarization programs relevant to tissue remodeling and immunoregulation, findings that are consistent with reduced innate immune responses and increased susceptibility to respiratory infections in smokers or CS-exposed individuals (2,5). Actions of CS on airway epithelial cells affect their production of inflammatory or host defense mediators (6)(7)(8)(9) and their interactions with DCs (10,11). Furthermore, direct actions of CS on DCs may affect DC maturation (12) and polarize T helper (Th) 2 immune responses (13,14).…”