Impaired Antiviral Stress Granule and IFN-β Enhanceosome Formation Enhances Susceptibility to Influenza Infection in Chronic Obstructive Pulmonary Disease Epithelium

Abstract

Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infections that result in exacerbations with exaggerated symptoms with increased mortality. The mechanisms underpinning this increased susceptibility to infection in COPD are unclear. In this study, we show that primary bronchial epithelial cells (pBECs) from subjects with COPD have impaired induction of type I IFN (IFN-β) and lead to heightened viral replication after influenza viral infection. COPD pBECs have reduced protein levels of protein kinase (PK) R and decreased formation of PKR-mediated antiviral stress granules, which are critical in initiating type I IFN inductions. In addition, reduced protein expression of p300 resulted in decreased activation of IFN regulatory factor 3 and subsequent formation of IFN-β enhanceosome in COPD pBECs. The decreased p300 induction was the result of enhanced levels of microRNA (miR)-132. Ectopic expression of PKR or miR-132 antagomiR alone failed to restore IFN-β induction, whereas cotreatment increased antiviral stress granule formation, induction of p300, and IFN-β in COPD pBECs. This study reveals that decreased induction of both PKR and p300 proteins contribute to impaired induction of IFN-β in COPD pBECs upon influenza infection.

MicroRNA-125a and -b inhibit A20 and MAVS to promote inflammation and impair antiviral response in COPD

“…We have previously shown that human influenza H3N2 infection induced heightened inflammatory responses (25), and high pathogenic avian H5N1is known to induce severe cytokine storms in the lung (9,26). We also showed that primary BECs (pBECs) from COPD subjects and our established in vivo model of experimental COPD have increased inflammatory and impaired antiviral responses to IAV infections, leading to more severe infection (27)(28)(29). Furthermore, miRNAs are known to be altered in COPD (30,31).…”

Microbiome effects on immunity, health and disease in the lung

“…The clinical course of COPD is complicated by frequent episodes of acute exacerbations, which primarily involves microbial and viral infections 91 , 126 , 127 . In the past two decades, our understanding of the pathogenesis of airway infections has increased substantially.…”

Decreased expression of type I (IFN-β) and type III (IFN-λ) interferons and interferon-stimulated genes in patients with chronic rhinosinusitis with and without nasal polyps

“…12 An abnormal innate immune response to VRIs has been reported to increase the susceptibility to viral infection in patients with chronic obstructive pulmonary disease (COPD), asthma, or cystic fibrosis, triggering disease exacerbation. [14][15][16][17][18] Airway epithelial cells from asthmatic patients produced less IFN-b and IFN-l and showed deficient innate immunity for rhinovirus infection. 14,16 IFN-b levels were also reduced in epithelial cells obtained from children with wheezing and atopy after respiratory syncytial virus infection.…”