Evasion of immune defenses
Having overcome the first layer of host lung defenses, NTHi must
also evade innate and adaptive immune responses. Pulmonary phagocytic
cells (alveolar macrophages and neutrophils) constantly sense the local
microenvironment for pathogen associated molecular patterns (PAMPs),
which are molecules with highly conserved motifs associated with human
pathogens. PAMPs bind to pattern recognition receptors, such as TLRs,
which activate intracellular pathways to secrete chemotaxins, including
IL-8 to recruit and upregulate neutrophils to the site of infection, and
to initiate intracellular killing of phagocytosed
pathogens.64 When phagocytes encounter NTHithere is a sustained release of ROS, both within intracellular
phagolysosomes and into the extracellular environment. The generation of
ROS is also associated with neutrophil and macrophage extracellular
traps (NETs and METs, respectively), which are composed of a mesh of
DNA, histones and bactericidal proteins to neutralize invading
pathogens. The production of ROS represents the primary mechanism
adopted by these cells to eliminate phagocytosed pathogens.
Nevertheless, NTHi can neutralize the effects of oxidative stress
by producing antioxidants, including catalase,
peroxiredoxin-glutaredoxin and superoxide dismutase (SOD), which in
addition to forming biofilms is one of the mechanisms it uses to resist
NET.
Furthermore, submucosal plasma cells produce dimeric IgA molecules,
which bind to an epithelial cell membrane protein, the secretory
component, and are transported through AECs to be released as secretory
IgA into mucosal secretions.67 IgA aids lung defenses
by preventing microbial adherence, neutralizing toxins and boosting
adaptive immunity. There are two types of IgA (IgA1 and IgA2) of which
IgA1 accounts for more than 90% of the total IgA. However, NTHiproduces an IgA1 protease, IgaA, encoded by the IgaA gene as an
extracellular endopeptidase that cleaves IgA1 at the hinge region,
disabling its antibacterial functions and aiding adherence to and
invasion of AECs. Approximately half the NTHi strains also
possess a second IgA1 protease gene, IgaB, that encodes IgaB,
which seems necessary for intracellular survival.
The human complement system is also part of the innate defenses against
pathogenic bacteria. It has multiple functions and when activated
complement mediates the inflammatory response and elimination of
pathogens and enhances adaptive immunity. The complement system leads to
C3b deposition on the bacterial cell surface with formation of the
membrane attack complex (MAC) and bacterial lysis. There are three
complement activation pathways, which can all be inhibited byNTHi . The classical and lectin pathways are blocked by the
C4b binding protein (C4bP),
whereas factor H is believed to be main inhibitor of the alternative
pathway. C4bP and factor H are captured by OMP P5 and protectNTHi against opsonization and phagocytosis, while also preventing
MAC formation. Vitronectin, a potent negative regulator of the terminal
pathway can also be bound by NTHI proteins E and F, further
inhibiting the formation of the MAC by NTHi . Moreover, LOS
covering the outer cell wall of NTHi can block bactericidal
antibodies accessing cell surface structures and activating the
classical complement pathway.73 Finally, NTHimay benefit from other co-pathogens, such as Moraxella
catarrhalis, and their inhibition of the complement
system.74