Research ArticleLung Disease

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

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Science Translational Medicine  28 Aug 2019:
Vol. 11, Issue 507, eaav3879
DOI: 10.1126/scitranslmed.aav3879

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Corticosteroid-driven bacterial load

Patients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to bacterial infections that can have deleterious consequences on disease outcome. The mechanisms modulating the susceptibility to infections in COPD are poorly understood. Inhaled corticosteroids (ICS) are standard treatment for COPD. Here, Singanayagam and colleagues show an association between ICS use and increased bacterial proliferation in lungs. In vitro and in vivo studies using human lung samples and mouse models demonstrated that the effect of ICS on bacterial infection was mediated by inhibition of the antimicrobial peptide cathelicidin. Blocking cathelicidin cleavage reduced the increased bacterial load associated with ICS administration in mice.

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 with Streptococcus 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.

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