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One of these potential pathogens, nontypeable <jats:italic>Haemophilus influenzae<\/jats:italic> (<jats:italic>NTHi<\/jats:italic>), adopts several, multifaceted redundant strategies to successfully colonize the lower airways and establish a persistent infection. <jats:italic>NTHi<\/jats:italic> can impair mucociliary clearance, express multiple multifunctional adhesins for various cell types within the respiratory tract and evade host defenses by surviving within and between cells, forming biofilms, increasing antigenic drift, secreting proteases and antioxidants, and by host\u2010pathogen cross\u2010talk, impair macrophage and neutrophil function. <jats:italic>NTHi<\/jats:italic> is recognized as an important pathogen in several chronic lower respiratory disorders, such as protracted bacterial bronchitis, bronchiectasis, cystic fibrosis, and primary ciliary dyskinesia. The persistence of <jats:italic>NTHi<\/jats:italic> in human airways, including its capacity to form biofilms, results in chronic infection and inflammation, which can ultimately injure airway wall structures. The complex nature of the molecular pathogenetic mechanisms employed by <jats:italic>NTHi<\/jats:italic> is incompletely understood but improved understanding of its pathobiology will be important for developing effective therapies and vaccines, especially given the marked genetic heterogeneity of <jats:italic>NTHi<\/jats:italic> and its possession of phase\u2010variable genes. 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