To summarize, the pathogenesis of disease due to nontypeable H. influenzae involves multiple steps and the interplay of a number of bacterial and host factors, as shown in Fig. 1. Following entry into the upper respiratory tract, bacteria encounter the mucociliary escalator. The P2 and P5 outer-membrane proteins and probably other factors promote bacterial binding to mucus, and elaboration of LOS causes damage to ciliated cells and impairs mucociliary function. Subsequently, several adhesins, including HMW1 and HMW2, pili, Hia, Hap, and others, mediate direct adherence to nonciliated epithelial cells. Cleavage of IgA1, invasion into cells and the subepithelial space, and phase and antigenic variation facilitate evasion of local immune mechanisms. Binding and uptake of iron and heme allow organisms to persist on the respiratory mucosa despite the relative scarcity of these nutrients. In the setting of a viral infection, allergic disease, or exposure to cigarette smoke, bacteria spread from the nasopharynx to other sites within the respiratory tract and produce symptomatic disease.