Osteopontin That Is Elevated in the Airways during COPD Impairs the Antibacterial Activity of Common Innate Antibiotics.

Anele Gela,Arne Egesten,Gopinath Kasetty,Heiko Herwald,Michiko Mori,Jonas S Erjefält,Matthias Mörgelin,Ravi K V Bhongir,Paul Keenan,Dominik Hartl

doi:10.1371/journal.pone.0146192

Anele Gela, Arne Egesten + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0146192

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Journal: PloS one	Publication Date: Jan 5, 2016
Citations: 15	License type: CC BY 4.0

Affiliation: Lund University

Abstract

Bacterial infections of the respiratory tract contribute to exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). There is also an increased risk of invasive pneumococcal disease in COPD. The underlying mechanisms are not fully understood but include impaired mucociliary clearance and structural remodeling of the airways. In addition, antimicrobial proteins that are constitutively expressed or induced during inflammatory conditions are an important part of the airway innate host defense. In the present study, we show that osteopontin (OPN), a multifunctional glycoprotein that is highly upregulated in the airways of COPD patients co-localizes with several antimicrobial proteins expressed in the airways. In vitro, OPN bound lactoferrin, secretory leukocyte peptidase inhibitor (SLPI), midkine, human beta defensin-3 (hBD-3), and thymic stromal lymphopoietin (TSLP) but showed low or no affinity for lysozyme and LL-37. Binding of OPN impaired the antibacterial activity against the important bacterial pathogens Streptococcus pneumoniae and Pseudomonas aeruginosa. Interestingly, OPN reduced lysozyme-induced killing of S. pneumoniae, a finding that could be explained by binding of OPN to the bacterial surface, thereby shielding the bacteria. A fragment of OPN generated by elastase of P. aeruginosa retained some inhibitory effect. Some antimicrobial proteins have additional functions. However, the muramidase-activity of lysozyme and the protease inhibitory function of SLPI were not affected by OPN. Taken together, OPN can contribute to the impairment of innate host defense by interfering with the function of antimicrobial proteins, thus increasing the vulnerability to acquire infections during COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is a serious medical condition where both its prevalence and mortality from the disease are increasing worldwide
Recent studies have demonstrated that many different AMPs such as lysozyme, lactoferrin, secretory leukocyte peptidase inhibitor (SLPI), midkine, defensins, thymic stromal lymphopietin (TSLP) and the cathelicidin-derived peptide LL37 are expressed in human airways where airway epithelial cells, submucosal glands, and recruited neutrophils are important cellular sources [11,12,13,14,15,16,17]
To OPN, lactoferrin and SLPI were detected in the bronchiolar epithelium and in the lumen, providing strong evidence that OPN co-localizes with AMPs expressed in the airway epithelium

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a serious medical condition where both its prevalence and mortality from the disease are increasing worldwide. Infections are an important cause of exacerbations where viruses and bacteria are estimated to play equal roles [3]. There is an increased risk of invasive pneumococcal disease (IPD) in COPD [6]. Despite the activation of innate immune mechanisms during the pathogenesis of COPD, which is evidenced by accumulation of inflammatory cells, chemokines and pro-inflammatory cytokines, infections trigger exacerbations in COPD [1]. This is likely due to a dysregulated and inappropriate host response [7, 8]. Antimicrobial proteins (AMPs) are important effector molecules of airway innate immunity [9]. Most AMPs are cationic with a net charge of

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