Abstract
Mucociliary airway clearance is an innate defense mechanism that protects the lung from harmful effects of inhaled pathogens. In order to escape mechanical clearance, airway pathogens including Streptococcus pneumoniae (pneumococcus) are thought to inactivate mucociliary clearance by mechanisms such as slowing of ciliary beating and lytic damage of epithelial cells. Pore-forming toxins like pneumolysin, may be instrumental in these processes. In a murine in vitro airway infection model using tracheal epithelial cells grown in air-liquid interface cultures, we investigated the functional consequences on the ciliated respiratory epithelium when the first contact with pneumococci is established. High-speed video microscopy and live-cell imaging showed that the apical infection with both wildtype and pneumolysin-deficient pneumococci caused insufficient fluid flow along the epithelial surface and loss of efficient clearance, whereas ciliary beat frequency remained within the normal range. Three-dimensional confocal microscopy demonstrated that pneumococci caused specific morphologic aberrations of two key elements in the F-actin cytoskeleton: the junctional F-actin at the apical cortex of the lateral cell borders and the apical F-actin, localized within the planes of the apical cell sides at the ciliary bases. The lesions affected the columnar shape of the polarized respiratory epithelial cells. In addition, the planar architecture of the entire ciliated respiratory epithelium was irregularly distorted. Our observations indicate that the mechanical supports essential for both effective cilia strokes and stability of the epithelial barrier were weakened. We provide a new model, where - in pneumococcal infection - persistent ciliary beating generates turbulent fluid flow at non-planar distorted epithelial surface areas, which enables pneumococci to resist mechanical cilia-mediated clearance.
Highlights
Pneumonia can be caused by various pathogens and is a leading cause of death due to infectious disease in industrialized countries [1]
Our results indicate that in pneumococcal airway infection, persistent ciliary beating together with an aberrant epithelial geometry impairs the hydrodynamics of mucociliary clearance
We argued that a mild overall reduction of the beat frequency - e.g. during initiation of airway disease by a limited number of pathogens - might be insufficient to inactivate the mucociliary clearance mechanism due to its complex hydrodynamic properties
Summary
Pneumonia can be caused by various pathogens (bacteria, viruses, fungi) and is a leading cause of death due to infectious disease in industrialized countries [1]. Pneumococci usually asymptomatically colonize the upper respiratory tract (nasopharynx) of humans [2]. They mainly exist as commensal bacteria along with other co-resident microorganisms [3]. Pneumococci pass to other areas where they can cause severe diseases (pathogenic stage). These include the lower airways/lungs (pneumonia), the middle ear (middle ear infections/ otitis media), the cerebrospinal fluid of the brain (meningitis), and the blood (bacteriaemia or septicemia), respectively [4,5]. Pneumococci are thought to follow similar strategies to attack ciliated respiratory and ciliated ependymal epithelia, the mechanisms that transform the persistently colonizing phenotype to an invasive pneumococcal disease with high morbidity and mortality are poorly understood
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