LOWER AIRWAY DEFENSES
The lung has layered defenses involving innate and adaptive immune
protection against infection. Airway epithelia, through their barrier
and MCC functions, production of antimicrobial peptides (AMPs),
inflammatory mediators, and ability to transport immunoglobulin (Ig) A
and IgM antibodies into the airway lumen, play a central role.
MCC is the main innate defense mechanism and involves mucus production
and its proximal transport by ciliary beating. The apical surfaces of
ciliated airway epithelial cells (AECs) are bathed by airway surface
liquid (ASL) comprised of an upper gel-like mucus layer composed
principally of MUC5AC and MUC5B mucins that entrap inhaled
microorganisms, and beneath it the periciliary fluid allowing rapid
ciliary beating. The mucus layer also secretes potent antimicrobial
molecules, such as lysozyme, defensins, IgA, and IgG. Respiratory cilia
are hair-like projections from the apical membranes of AECs that, by
beating synchronously, propel airway mucus and entrapped microorganisms
towards the oropharynx, where they are either expectorated or
swallowed.21 Respiratory cilia may also have
chemosensory, signal transduction, and cellular growth regulatory
functions. They express members of the bitter taste family of receptors
to direct innate immune defenses responding to foreign antigens.
Microorganisms penetrating the mucus layer reach a second line of
defense that includes AMPs secreted by AECs that are activated after
sensing microbes by pattern recognition receptors, such as Toll-like
receptors (TLR). AMPs, like lysozyme and lactoferrin, are also expressed
constitutively into the ASL and are now supplemented locally by
defensins and other AMPs, cytokines, and chemokines from recruited
phagocytes and activated AECs. AMPs selectively target vital microbial
structures, taking advantage of structural and biochemical differences
between the host and the microbes. Microorganisms resistant to AMPs are
killed by reactive oxygen species (ROS) produced by neutrophils and
alveolar macrophages.
The third line of defense is adaptive immunity mediated by B-lymphocytes
(humoral immunity) and T-lymphocytes (cellular immunity) where clonal
rearrangement of antigen receptor genes generates long-term
antigen-specific memory. The importance of adaptive immunity is
underlined by congenital and acquired disorders of adaptive immunity,
such as agammaglobulinemia, common variable immunodeficiency, and human
immunodeficiency virus infections, which are all risk factors for
recurrent pneumonia and bronchiectasis. Establishment of a new pathogen
in the lower airways requires them to evade these defenses, to compete
with other resident microbes, and to adapt to the nutrient availability
and physicochemical properties of the local microenvironment. Here we
describe how NTHi adapt to survive in the lungs of children with
CSLD, where they exploit impaired local defenses and contribute to
airway wall injury.