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).