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Role of two paralogous proteins in Bordetella pathogenesis.

Members of the bacterial genus Bordetella are respiratory pathogens of humans and animals. B. pertussis infects only humans and is the etiologic agent of the acute respiratory disease known as whooping cough. B. parapertussis can infect both humans and sheep. In contrast, B. bronchiseptica has a broad host range and infects pigs, cats, dogs, rabbits and occasionally humans. The majority of virulence determinants of the Bordetella infectious cycle is regulated by the BvgAS signal transduction system, wherein BvgS is the transmembrane sensor kinase and BvgA is the DNA binding response regulator. We recently identified an open reading frame, bcfA that has sequence similarity to the previously identified bipA gene of Bordetella. Our preliminary results suggest that bcfA is activated by BvgAS. We have identified multiple sequence elements resembling the consensus BvgA binding site in the bcfA promoter region. Using Electrophoretic Mobility Shift Assays, we have demonstrated direct binding of purified BvgA to the bcfA promoter. Additionally, our preliminary results demonstrate that individual deletion of either bipA or bcfA does not have any significant effect on respiratory tract colonization by Bordetella. Strikingly, we have found that concomitant deletion of bipA and bcfA results in a defect in colonization of the rat trachea, thereby suggesting a potential role for these two proteins in Bordetella pathogenesis. Thus, the focus of my project is to assess the BvgAS-mediated regulation of bcfA and to discern the role of BipA and BcfA in respiratory tract colonization by Bordetella.