Collections > Electronic Theses and Dissertations > Cigarette smoke alters influenza induced immune responses of the respiratory epithelium
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Epidemiological evidence demonstrates that smokers are at increased risk for and suffer greater morbidity and mortality from influenza infection but the mechanism underlying this susceptibility is poorly understood. Previous work from our laboratory confirmed that smokers have increased markers of influenza infection using both in vivo and in vitro models of influenza infection. In this dissertation, the differential nasal immune responses to influenza infection were explored in nonsmokers and smokers. In the in vitro model of influenza infection, nasal epithelial cells (NEC) obtained from nonsmokers and smokers were differentiated ex vivo and co-cultured with monocyte-derived dendritic cells (mono-DCs) from nonsmokers to determine the effect of cigarette smoke (CS) exposure on the ability of NEC to communicate with underlying DCs. These co-cultures were then infected with influenza A virus. Both NEC from smokers and mono-DCs co-cultured with smoker NEC had decreased expression of antiviral mediators interferon regulatory factor 7 (IRF7) and Th1 cell chemokine interferon gamma-induced protein 10 kDa (IP-10) with increased expression of Th2 chemokine thymic stromal lymphopoeitin (TSLP). Thus, CS exposure altered antiviral defense mechanisms in both NEC and mono-DCs and changed the nature of communication between these two cell types. In the in vivo model of human influenza infection, nonsmokers and smokers were administered live attenuated influenza virus (LAIV) and the resulting localized nasal immune responses were monitored using nasal lavages and nasal biopsies. Natural killer (NK) cell cytotoxic responses and chemokines important for NK cell activation were suppressed in smoker nasal lavages. This data was intriguing because 1) it was the first documentation of NK cells in the nasal lavage cell population and 2) decreased NK cell activity in smokers could contribute to delayed influenza virus clearance. These data were also the first to show that γδ T intraepithelial lymphocytes, a rare immune cell type, migrated to the nasal mucosa following LAIV inoculation in both nonsmokers and smokers. Together these data demonstrate that CS exposure suppresses NK, NEC, and DC specific immune responses of the respiratory mucosa and contribute to the mechanism of increased susceptibility to respiratory viruses observed in CS exposed populations.