For most common respiratory viruses in humans, respiratory epithelium is the primary target. Cigarette smoke-induced alter in epithelial function have a major impact on respiratory host resistance and are important in influencing the final outcome of infection. However, it is unknown whether tobacco alternatives have similar effects on epithelial host resistance responses. This project will identify genomic biomarkers of smoke exposure associated with tobacco alternatives from nasal epithelial cell samples obtained from 240 adults (aged 18-45) and will estimate respiratory host defense in subjects infected with live attenuated influenza virus. The main theme is as follows: (1) To use superficial nasal scrape biopsies to compare genomic and epigenomic signatures induced in epithelial cells following exposure to cigarette smoking and tobacco alternatives (2) To use an in vitro model of differentiated human nasal epithelial cells to compare host defense responses following exposure to cigarette smoke and tobacco alternatives and (3) To compare influenza-induced responses in cigarette smokers, hookah smokers and e-cigarette smokers in vivo. This research will provide new information about the impact of new and emerging tobacco products on respiratory resist systems.