Adherence to AECs
Having bypassed MCC defenses, NTHi employs multiple surface-expressed multifunctional adhesion proteins, such as proteins E and F, that bind to nonciliated AECs and extracellular matrix (ECM) proteins, in particular laminin and vitronectin. Adherence is enhanced when there is structural damage to the airway mucosa from viral infections or chronic inflammation exposing ECM proteins. The trimeric autotransporters, Hi adhesin (Hia), Hi adhesion protein (Hap), and high–molecular weight (HMW) proteins 1 and 2, play an important role in colonization, even though only Hap is highly conserved in NTHistrains. Moreover, the type IV pili on NTHi cell surfaces mediate adherence to AECs by interacting with the intracellular adhesion molecule-1 (ICAM-1), which also serves as a cellular receptor for rhinoviruses that may help explain their frequent co-infections. The ICAM-1 receptors on the AEC surface increase in numbers in COPD patients, in smokers, and exhibit a positive feedback loop followingNTHi exposure. Additionally, P1 fimbriae bind to the carcinoembryonic antigen-related cell adhesion molecule (CEACAM-1), while P5 fimbriae adhere to both CEACAM-1 and ICAM-1 on AEC surfaces, respectively.59,60 As well as binding to mucins, other OMPs adhere to exposed ECM proteins.61 Indeed, the interaction between the ECM exposed within the COPD airway environment and Hap facilitates NTHi attachment to AECs and this interaction may also operate in the lungs of children with CSLD.