Abstract
BackgroundFilamentous hemagglutinin (FHA) is a cell-associated and secreted adhesin produced by Bordetella pertussis with pro-apoptotic and pro-inflammatory activity in host cells. Given the importance of the NF-κB transcription factor family in these host cell responses, we examined the effect of FHA on NF-κB activation in macrophages and bronchial epithelial cells, both of which are relevant cell types during natural infection.Methodology/Principal FindingsExposure to FHA of primary human monocytes and transformed U-937 macrophages, but not BEAS-2B epithelial cells, resulted in early activation of the NF-κB pathway, as manifested by the degradation of cytosolic IκBα, by NF-κB DNA binding, and by the subsequent secretion of NF-κB-regulated inflammatory cytokines. However, exposure of macrophages and human monocytes to FHA for two hours or more resulted in the accumulation of cytosolic IκBα, and the failure of TNF-α to activate NF-κB. Proteasome activity was attenuated following exposure of cells to FHA for 2 hours, as was the nuclear translocation of RelA in BEAS-2B cells.ConclusionsThese results reveal a complex temporal dynamic, and suggest that despite short term effects to the contrary, longer exposures of host cells to this secreted adhesin may block NF-κB activation, and perhaps lead to a compromised immune response to this bacterial pathogen.
Highlights
Despite widespread vaccination against Bordetella pertussis (B. pertussis), whooping cough is reemerging in most parts of the world
Filamentous hemagglutinin (FHA) induces rapid degradation of IkBa in macrophages but not in epithelial cells We analyzed the effect of FHA on the NF-kB transcriptionfactor pathway by incubating U-937 monocyte-derived macrophages, fresh human monocytes or the human bronchial epithelial cell line BEAS-2B with 5 mg/ml FHA for up to 16 hours (Fig. 1A, 1B 1C)
IkBa cytosolic levels in monocyte-derived cells treated for various periods of time (0–8 hours) with 5 mg/ml FHA suggested rapid degradation of IkBa, observable within 30 minutes in U-937 macrophages (Fig. 1A) and in fresh monocytes (Fig. 1B)
Summary
Despite widespread vaccination against Bordetella pertussis (B. pertussis), whooping cough is reemerging in most parts of the world. B. pertussis colonizes the mucosa of the respiratory tract, where it interacts with ciliated bronchial epithelial cells and local immune cells, causing a highly contagious and prolonged respiratory disease [1]. Filamentous hemagglutinin (FHA) is a 220 kDa protein associated with the bacterial surface, and secreted in substantial amounts [2]. Studies using FHA-deficient B. pertussis strains implicate this protein in tracheal colonization, cell adherence [3] and invasion [4] of macrophages and epithelial cells by B. pertussis. Filamentous hemagglutinin (FHA) is a cell-associated and secreted adhesin produced by Bordetella pertussis with pro-apoptotic and pro-inflammatory activity in host cells. Given the importance of the NF-kB transcription factor family in these host cell responses, we examined the effect of FHA on NF-kB activation in macrophages and bronchial epithelial cells, both of which are relevant cell types during natural infection
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