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

Abstract

BackgroundPatients 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.MethodsWe 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.ResultsFrequent 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.ConclusionThese 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.

Joint Clinical and Molecular Subtyping of Copd With Variational Autoencoders

“…Among the most significant differences, we found several pathways related to immune response and regulation, including Interferon Alpha response, IL6/JAK/STAT3 Signaling and TNF-α Signaling via NF-κB. COPD patients who experience frequent exacerbations have been reported to exhibit reduced IFN-α levels in response to viral infection compared to individuals with lower exacerbation rates [62]. As such, downregulation of the IFN-α in the MOD branch might indicate compromised antiviral immunity, potentially leading to a higher susceptibility to exacerbations.…”

Respiratory Viral Infections in Exacerbation of Chronic Airway Inflammatory Diseases: Novel Mechanisms and Insights From the Upper Airway Epithelium

“…Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance (Hammond et al, 2015;McKendry et al, 2016;Akbarshahi et al, 2018;Gill et al, 2018;Wang et al, 2018;Singanayagam et al, 2019b). Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells (Becker, 2006;McKendry et al, 2016).…”

“…Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection (Chi et al, 2011;Ford et al, 2013;Papi et al, 2013). The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance (Kim et al, 2008;Hammond et al, 2015;Hewitt et al, 2016;McKendry et al, 2016;Singanayagam et al, 2019b). The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.…”

Mechanisms of Virus-Induced Airway Immunity Dysfunction in the Pathogenesis of COPD Disease, Progression, and Exacerbation

“…Although accumulated CD8 + T cells are present in greater numbers in severe COPD, a diminished CD8 + T cell antiviral response, worsened airflow limitation and respiratory symptoms have been reported in IAV and HRV-induced COPD exacerbations (68,71,76,77). As a result, CD8 + cells potentially amplify airway epithelium destruction and promote tissue injury through mechanisms including direct cytotoxic effects, pro-inflammatory signaling and recruitment of other immune cells, leading to increased susceptibility to virus infections of airway epithelium (42-44, 69).…”