PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) is a progressive pulmonary disease characterized by frequent episodes of acute deterioration termed acute exacerbations of COPD (AECOPD). The underlying biological mechanisms and risk profiles contributing to AECOPD are poorly understood. The nasal mucosal environment, including the inflammatory state and nasal microbiome, play a role in host defenses against viral infections. Susceptibility to viral infections, a trigger of AECOPD, is a potential mechanism for the COPD frequent exacerbator phenotype. Our research group has established approaches to rigorously characterize and quantify the nasal mucosal immune environment and microbiome, as well as determine the functional status of the nasal immune environment with a controlled Live Attenuated Influenza Vaccine (LAIV) exposure. Our overall objective is to determine the immune alterations and functional implications of changes in the nasal immune environment and microbiome present in individuals with frequent AECOPD. We hypothesize that dysfunctional nasal immunity underlies the frequent AECOPD phenotype and therefore presents a novel mechanism of increased AECOPD risk. We hypothesize that these immune alterations will impact responses to controlled viral infection and could predict the course of naturally occurring AECOPD. We will define the nasal immune environment (Aim 1) and microbiome (Aim 2) of frequent exacerbators, infrequent exacerbators, and healthy non-smokers, using cluster analyses to define the nasal “biological fingerprint” of the frequent AECOPD phenotype. Through longitudinal assessments embedded in these Aims we will define the variations of these measures during stable state and during AECOPD. We will then use a Live Attenuated Influenza Vaccine (LAIV) model to determine the functional implications of differences in the respiratory immune environment of frequent and infrequent exacerbators during a controlled viral challenge (Aim 3). Successful completion of these aims will lead to the first rigorous characterization of the nasal mucosal and microbiome changes associated with frequent exacerbators of COPD, validate these findings in a controlled experimental setting, and advance a novel hypothesis that the frequent exacerbator phenotype arises from altered nasal immune responses and microbiome constitution.