Abstract
Pertussis toxin (PTx), the major virulence factor of the whooping cough-causing bacterial pathogen Bordetella pertussis, permeabilizes the blood–brain barrier (BBB) in vitro and in vivo. Breaking barriers might promote translocation of meningitis-causing bacteria across the BBB, thereby facilitating infection. PTx activates several host cell signaling pathways exploited by the neonatal meningitis-causing Escherichia coli K1-RS218 for invasion and translocation across the BBB. Here, we investigated whether PTx and E. coli K1-RS218 exert similar effects on MAPK p38, NF-κB activation and transcription of downstream targets in human cerebral endothelial TY10 cells using qRT-PCR, Western blotting, and ELISA in combination with specific inhibitors. PTx and E. coli K1-RS218 activate MAPK p38, but only E. coli K1-RS218 activates the NF-κB pathway. mRNA and protein levels of p38 and NF-κB downstream targets including IL-6, IL-8, CxCL-1, CxCL-2 and ICAM-1 were increased. The p38 specific inhibitor SB203590 blocked PTx-enhanced activity, whereas E. coli K1-RS218’s effects were inhibited by the NF-κB inhibitor Bay 11-7082. Further, we found that PTx enhances the adherence of human monocytic THP-1 cells to human cerebral endothelial TY10 cells, thereby contributing to enhanced translocation. These modulations of host cell signaling pathways by PTx and meningitis-causing E. coli support their contributions to pathogen and monocytic THP-1 cells translocation across the BBB.
Highlights
Pertussis toxin (PTx), the major virulence factor secreted by the Gram-negative bacteriumBordetella pertussis, is systemically distributed and essential for the onset of the acute respiratory disease whooping cough [1,2,3,4,5,6]
In our previous study we demonstrated that PTx induces similar host cell signaling pathways as E. coli K1 in endothelial cells of the BBB, thereby enhancing invasion and translocation of E. coli K1-RS218 [17]
We showed that PTx exhibited host cell signaling events similar to those induced by E. coli
Summary
Pertussis toxin (PTx), the major virulence factor secreted by the Gram-negative bacteriumBordetella pertussis, is systemically distributed and essential for the onset of the acute respiratory disease whooping cough [1,2,3,4,5,6]. Pertussis can be accompanied by secondary infections and additional serious complications including even neurologic disorders as a concomitant manifestation [11,12,13]. It is debated whether these complications might be associated with PTx, as the toxin enhances the permeability of the blood–brain-barrier (BBB) in vitro and potentially in vivo. Some authors even discuss a possible link of subclinical pertussis to the development of multiple sclerosis [18] It appears that by facilitating and enhancing the traversal of immune cells and of pathogens across the blood-brain barrier, the activities of PTx during pertussis infection might create a predisposition for additional bacterial infections of the CNS. PTx is a typical A-B5 bacterial toxin [19,20] where the enzymatically active
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