Cooperative roles for fimbria and filamentous hemagglutinin in Bordetella adherence and immune modulation

Bordetella fimbriae (FIM) are generally considered to function as adhesins despite a lack of experimental evidence supporting this conclusion for Bordetella pertussis and evidence against a requirement for FIM in adherence of Bordetella bronchiseptica to mammalian cell lines. Using B. bronchiseptica and mice, we developed an in vivo adherence assay that revealed that FIM do function as critically important adhesins in the lower respiratory tract. In the first few days postinoculation, FIM-deficient B. bronchiseptica induced a more robust inflammatory response than wild-type bacteria did, suggesting that FIM, like filamentous hemagglutinin (FHA), allow B. bronchiseptica to suppress the innate immune response to infection. Localization analyses indicated that FIM are required for efficient attachment to airway epithelium, as bacteria lacking FIM localized to alveoli. FHA-deficient bacteria, in contrast, localized to airways. Bacteria unable to produce both FIM and FHA localized to alveoli and caused increased inflammation and histopathology identical to that caused by FIM-deficient bacteria, demonstrating that lack of FIM is epistatic to lack of FHA. Coinoculation experiments provided evidence that wild-type B. bronchiseptica suppresses inflammation locally within the respiratory tract and that both FHA and FIM are required for defense against clearance by the innate immune system. Altogether, our data suggest that FIM-mediated adherence to airway epithelium is a critical first step in Bordetella infection that allows FHA-dependent interactions to mediate tight adherence, suppression of inflammation, and resistance to inflammatory cell-mediated clearance. Our results suggest that mucosal antibodies capable of blocking FIM-mediated interactions could prevent bacterial colonization of the lower respiratory tract. Although fimbriae (FIM) have been shown to be important mediators of adherence for many bacterial pathogens, there is surprisingly little experimental evidence supporting this role for Bordetella fimbria. Our results provide the first demonstration that Bordetella FIM function as adhesins in vivo, specifically to airway epithelium. Furthermore, our results suggest that FIM mediate initial interactions with airway epithelial cells that are followed by tight filamentous hemagglutinin (FHA)-mediated binding and that together, FIM and FHA allow Bordetella to suppress inflammation, leading to prolonged colonization. Given the shortcoming of the current ace