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Bordetella pertussis , Bordetella bronchiseptica , and Bordetella parapertussis share highly homologous virulence factors and commonly cause respiratory infections in mammals; however, their host specificities and disease severities differ, and the reasons for this remain largely unknown. Adenylate cyclase toxin (CyaA) is a homologous virulence factor that is thought to play crucial roles in Bordetella infections. We herein demonstrate that CyaAs function as virulence factors differently between B. bronchiseptica / B. parapertussis and B. pertussis  B  bronchiseptica CyaA bound to target cells, and its enzyme domain was translocated into the cytosol similarly to B  pertussis CyaA. The hemolytic activity of B  bronchiseptica CyaA on sheep erythrocytes was also preserved. However, in nucleated target cells, B  bronchiseptica CyaA was phosphorylated at Ser 375 , which constitutes a motif (RSXpSXP [pS is phosphoserine]) recognized by the host factor 14-3-3, resulting in the abrogation of adenylate cyclase activity. Consequently, the cytotoxic effects of B  bronchiseptica CyaA based on its enzyme activity were markedly attenuated. B  parapertussis CyaA carries the 14-3-3 motif, indicating that its intracellular enzyme activity is abrogated similarly to B  bronchiseptica CyaA; however, B  pertussis CyaA has Phe 375 instead of Ser, and thus, was not affected by 14-3-3. In addition, B  pertussis CyaA impaired the barrier function of epithelial cells, whereas B  bronchiseptica CyaA did not. Rat infection experiments suggested that functional differences in CyaA are related to differences in pathogenicity between B. bronchiseptica / B  parapertussis and B. pertussis  IMPORTANCE  Bordetella pertussis , B. bronchiseptica , and B. parapertussis are bacterial respiratory pathogens that are genetically close to each other and produce many homologous virulence factors; however, their host specificities and disease severities differ, and the reasons for this remain unknown. Previous studies attempted to explain these differences by the distinct virulence factors produced by each Bordetella species. In contrast, we indicated functional differences in adenylate cyclase toxin, a homologous virulence factor of Bordetella The toxins of B. bronchiseptica and presumably B. parapertussis were inactivated by the host factor 14-3-3 after phosphorylation in target cells, whereas the B. pertussis toxin was not inactivated because of the lack of the phosphorylation site. This is the first study to show that 14-3-3 inactivates the virulence factors of pathogens. The present results suggest that pathogenic differences in Bordetella are attributed to the different activities of adenylate cyclase toxins.

The Eukaryotic Host Factor 14-3-3 Inactivates Adenylate Cyclase Toxins of Bordetella bronchiseptica and B. parapertussis, but Not B. pertussis