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.