Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease

Abstract

Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion withStreptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp−/−) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.

Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon

“…Existing data indicate that ACE2 is expressed primarily in the nasal and bronchial epithelium and is absent from immune cells (16). Given our prior data indicating that FP also exerts its inhibitory effects on immunity principally at the pulmonary epithelium (8,23), we next assessed whether suppressive effects on ACE2 were also observed following ex vivo ICS administration in cultured COPD bronchial epithelial cells (BECs, Fig 5a). Baseline characteristics of the subjects included in these analyses are shown in table 2.…”

“…Primary cells were cultured in collagen coated T75 flasks in LH-9 medium until 80% confluent before being seeded at 2.5 x 10 5 cells per well in a 24-well plate. Cells were treated with 10nM FP (Sigma-Aldrich) or vehicle dimethyl sulfoxide (DMSO), as previously reported (23).…”

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

“…Murray et al (2006) has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance (Kim et al, 2008;Stolz et al, 2019) in particular the late onset of a bacterial infection (Singanayagam et al, 2018(Singanayagam et al, , 2019a. In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.…”

“…Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth (Siegel et al, 2014;Mallia et al, 2018). Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms (Singanayagam et al, 2018(Singanayagam et al, , 2019aWang et al, 2018;Finney et al, 2019). All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles (Teo et al, 2018).…”

Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): Review of mechanisms that underlie risks

“…Existing evidence supports the former of these 2 mechanisms as evaluation of the in vivo effects of ICSs in animal models and patients with COPD has indicated disruption of the endogenous microbiota with increased relative abundance of the genus Streptococcus. 8 Using mouse models to understand cause and effect, we identified that impairment of lung bacterial control by ICSs occurs mechanistically through suppression of epithelial production of the antimicrobial peptide cathelicidin. 8 In contrast to wild-type mice, FP had no effect on bacterial loads in Streptococcus pneumoniae-infected cathelicidin-deficient (Camp 2/2 ) mice, whereas recombinant cathelicidin protein could reverse FP-mediated increases in Streptococci within the microbiota, indicating that cathelicidin is necessary and sufficient for FP to impart its adverse effects on host defense.…”