Anti-microbial immunity is impaired in COPD patients with frequent exacerbations

Singanayagam, Aran; Loo, Su-Ling; Calderazzo, Maria; Finney, Lydia J; Trujillo Torralbo, Maria-Belen; Bakhsoliani, Eteri; Girkin, Jason; Veerati, Punnam; Pathinayake, Prabuddha S; Nichol, Kristy S; Reid, Andrew; Foottit, Joseph; Johnston, Sebastian L; Bartlett, Nathan W; Mallia, Patrick

Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) sub-group requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. Ex vivo immune responses to rhinovirus infection in differentiated bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the anti-viral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. RV-induction of interferon and ISGs ex vivo was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators also had reduced sputum levels of the anti-microbial peptide mannose-binding lectin (MBL)-2 with an associated increase in sputum bacterial loads at 2 weeks following virus-associated exacerbation onset. MBL-2 levels correlated negatively with bacterial loads during exacerbation. These data implicate deficient airway innate immunity in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention/treatment of frequent exacerbations.