Abstract
The bronchial epithelium provides protection against pathogens from the inhaled environment through the formation of a highly-regulated barrier. In order to understand the pulmonary diseases melioidosis and tularemia caused by Burkholderia thailandensis and Fransicella tularensis, respectively, the barrier function of the human bronchial epithelium were analysed. Polarised 16HBE14o- or differentiated primary human bronchial epithelial cells (BECs) were exposed to increasing multiplicities of infection (MOI) of B. thailandensis or F. tularensis Live Vaccine Strain and barrier responses monitored over 24–72 h. Challenge of polarized BECs with either bacterial species caused an MOI- and time-dependent increase in ionic permeability, disruption of tight junctions, and bacterial passage from the apical to the basolateral compartment. B. thailandensis was found to be more invasive than F. tularensis. Both bacterial species induced an MOI-dependent increase in TNF-α release. An increase in ionic permeability and TNF-α release was induced by B. thailandensis in differentiated BECs. Pretreatment of polarised BECs with the corticosteroid fluticasone propionate reduced bacterial-dependent increases in ionic permeability, bacterial passage, and TNF-α release. TNF blocking antibody Enbrel® reduced bacterial passage only. BEC barrier properties are disrupted during respiratory bacterial infections and targeting with corticosteroids or anti-TNF compounds may represent a therapeutic option.
Highlights
The lung epithelium forms the first line of defence against inhaled pathogens and, through regulation of epithelial barrier functions, it is a key player in maintaining tissue homeostasis [1]
We show that B. thailandensis and F. tularensis both disrupt the physical barrier resulting in their passage from the apical to the basolateral epithelial surface and activation of the immunological barrier with induction of TNF-α release
Prior to exposing epithelial cells to bacteria, growth of the bacteria in epithelial culture medium was assessed. Both B. thailandensis and F. tularensis were able to proliferate in airway epithelial culture was assessed. Both B. thailandensis and F. tularensis were able to proliferate in airway epithelial culture medium (Figure S1), F. tularensis Live Vaccine Strain (LVS) showed slower growth rates in the first 5 h (up to medium (Figure S1), F. tularensis LVS showed slower growth rates in the first 5 h
Summary
The lung epithelium forms the first line of defence against inhaled pathogens and, through regulation of epithelial barrier functions, it is a key player in maintaining tissue homeostasis [1]. Key components in anti-microbial defence are secreted by bronchial epithelial cells (BECs) into the mucus layer and include defensins, nitric oxide (NO), and reactive oxygen species (ROS) [2]. Pathogens 2016, 5, 53 is mainly composed of hydrated mucins that provide viscosity and enables entrapment of bacteria, which are transported out of the lungs to the hypopharynx via the action of ciliated epithelial cells within the mucociliary escalator. Commensal bacteria are adapted to these epithelial defence mechanisms and a stable microflora can develop without causing any inflammation. Some pathogenic bacteria can overcome the anti-microbial defence mechanisms of the epithelium and cause symptomatic infections [3]. Tularaemia is endemic in Scandinavia and North America with 30%–60% mortality following exposure to the most pathogenic strains, if left untreated [4]
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