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.