HOW NTHi ESTABLISHES LOWER AIRWAY INFECTION
Following either inhalation of respiratory droplets or micro-aspiration and mucosal dispersion from the upper to lower airways, NTHiemploys several strategies to establish infection: perturbation of MCC, adherence to AECs, evading immune defenses, forming biofilms, and scavenging iron and other essential nutrients, allowing them to persist and survive in the lungs (Figure-1).
Perturbation of MCC NTHi colonization is facilitated by impaired MCC. Such impairment may be congenital, as in CF or PCD, or acquired following exposure to respiratory viruses, chronic inflammation, cigarette smoke, indoor air pollution or NTHi itself. In CF, mutations in the CF transmembrane conductance regulator (CFTR) chloride channel compromise MCC by decreasing chloride and bicarbonate secretion into the ASL, thereby reducing its volume and pH, increasing mucus viscosity, and impeding ciliary function. While in PCD, mutations in motile ciliopathy-associated genes result in AECs with dyskinetic or static cilia.
Respiratory viruses, notably rhinoviruses, respiratory syncytial virus and influenza, downregulate genes critically involved in cilia formation through an ill-defined mechanism.Moreover, viruses can lead to shedding of ciliated AECs or dysregulated cilial function, further reducing MCC and increasing the risk of secondary bacterial infection. Rhinovirus challenge studies in adults with chronic obstructive pulmonary disease (COPD) induced bacterial co-infection in 60% of subjects compared with 10% of healthy, non-smoking controls. NTHi was the principal secondary bacterial pathogen, with bacterial load peaking at 2-weeks and persisting for at least 6-weeks after the rhinovirus infection. Possible mechanisms for secondary NTHi infections are that rhinoviruses disrupt AEC barrier function by damaging tight inter-epithelial cell junctions, permitting NTHi to enter paracellular sites.Rhinoviruses andNTHi also share a common cellular receptor and rhinoviruses inhibit macrophage interleukin (IL)-1 responses to NTHi and diminish IL-8 responses via TLR-2 dependent degradation of IRAK-1.
CSLD in children is characterized by chronic airway inflammation, which may also adversely impact upon MCC. Chronic inflammation in asthma is associated with decreased cilial motility, disorientated beating direction, and ultrastructural damage. In COPD, the intraflagellar transport of structural proteins in the respiratory cilia is dysregulated; consequently, cilia length is shortened and less capable of propelling the overlying mucus.Furthermore, in adults with COPD, squamous cells replace pseudostratified epithelia, resulting in a significant reduction in ciliated cuboidal cell numbers. Cigarette smoke exposure also has detrimental effects upon ciliogenesis and cilia function,decreasing CFTR activity, and it is associated with decreased ciliary beat frequency. Nevertheless, it is difficult to disentangle the relationships between inflammation, infection, resident lung microbiota, and aerotoxicants, and their individual impact upon MCC.
Experimental models indicate NTHi may also interfere with MCC directly. NTHi adheres initially to the mucus layer via its outer membrane proteins (OMP), such as P2 and P5, following which isolates expressing the highly conserved surface lipoprotein, protein-D, and lipo-oligosaccharide (LOS) inhibit cilial function. Activation of the host protein, protein kinase C epsilon, mediates these effects, but this is an inconsistent finding, and penetrating paracellular foci is also thought to be an important strategy for escaping the mucociliary apparatus.