Bordetella virulence gene regulation in mammalian hosts

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DESCRIPTION (provided by applicant): Members of the Bordetella genus provide superior experimental model systems for studying bacterial-host interactions. The continued presence of B. pertussis and B. parapertussis despite widespread vaccinations and the gradual reemergence of the disease in a number of countries emphasize the need to attain a detailed understanding of the molecular determinants of Bordetella infections. The BvgAS signal transduction system regulates the majority of virulence determinants involved in the Bordetella infectious cycle. BvgAS controls the expression of a spectrum of gene expression states in response to incremental differences in the intensity of environmental signals. Although detailed information is available about the range of gene expression patterns mediated by the BvgAS locus, little is known about the pattern of gene expression during the infectious cycle. We believe that a concerted spatial and temporal expression of virulence factors in the respiratory tract, allows Bordetella to establish long-term persistence within hosts. Our long-term goal is to understand the detailed molecular mechanisms controlling the versatility in expression of virulence factors during host colonization. As a necessary first step towards this goal, we propose to determine the transcriptional profile of Bvg-regulated genes during the infectious cycle. We will determine how Bordetella genes are regulated in different respiratory tissues and during multiple time-points of the infectious cycle by using the widely studied and well-characterized rodent models of Bordetella infections and by Real Time RT PCR analyses and measurement of GFP fluorescence. Deciphering the complexities of this regulation would unravel new information that would ultimately lead to a better understanding of the mechanisms employed by organisms of the Bordetella species to survive within mammalian hosts. In addition to enhancing our understanding of the molecular mechanisms involved in Bordetella infection, our results should contribute to the development of therapy against a wide variety of respiratory-tract pathogens, which utilize similar strategies to cause disease.