NTHi-induced host damage
Incursion by NTHi into the lower airways induces both innate and
adaptive immune responses. NTHi infection stimulate TLRs and
NLR family pyrin domain
containing 3 (NLRP3) inflammasomes stimulate AECs to release AMPs and
proinflammatory mediators, including tumor necrosis factor-alpha, IL-6
and IL-8, that recruit and activate macrophages and neutrophils leading
to increased ROS production, and NETs formation, the latter designed to
immobilize and destroy pathogens. In this hyperinflammatory environment,
high concentrations of proteolytic enzymes, such as neutrophil elastase,
and ROS are released by activated and dying neutrophils, with the latter
leading to local increases in free radicals. Despite these host
defensive measures, NTHi are resistant to NETs and survive
oxidative stress by forming biofilms and possessing antioxidants, while
also capitalizing on the ROS-induced tissue damage as a nutrient source
to establish and sustain their presence in the airways. The tissue
damage results from excessive oxidative stress secondary to NTHipersistence and an imbalance between oxidants and antioxidants, leading
to oxidation-induced damage of proteins, lipids, and DNA in the airways.
These changes, labelled by some as NETosis, contribute to a pathway
leading to impaired lung function and destruction of local airway wall
architecture as demonstrated by airway hyperresponsiveness, mucus
hypersecretion, AEC shedding, vascular exudation, and, finally, airway
remodeling. Moreover, the damaged mucosa facilitates NTHipersistence because of further disruption to MCC and the higher affinity
of NHTi for damaged tissues, which sustains the airway
inflammatory response and promotes a vicious cycle of infection,
inflammation and impaired bacterial clearance. (Figure-3).