MODELING AIRWAY RESPONSE TO BORDETELLA SP INFECTION

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DESCRIPTION (Applicant's Abstract): Although vaccination introduced in the late 1940s has been effective in reducing the incidence of Bordetella disease in humans, the disease is still endemic, and affects more than 60 million people annually. In the United States, the reported incidence of Bordetella disease is low, with 2,000 - 6,000 diagnosed cases each year. However, this number is an underestimate due to the difficulty of diagnosis, and Bordetella disease has been steadily increasing in immunocompromised and adult populations since the late 1970s. This research is directed at the understanding of Bordetella derived factors and their impact on the initiation and the progression of airway cell pathogenesis. The interaction between bacterial pathogens and their hosts can range from the establishment of a commensal relationship to a potentially lethal disease. During pathogenesis, bacteria continually monitor their environment and adjust virulence gene expression accordingly. It is thought pathogens from Bordetella sp. express specific gene products that allow for preferential binding of ciliated cells in the airway epithelium. Furthermore, it is suggested that this binding initiates host cell signaling pathways-including transient changes in intracellular Ca2+ concentration ([Ca2+]i)-and host cell cytoskeleton rearrangements that help establish a favorable local environment for the establishment and progression of Bordetella sp. infection. In this proposal, primary cultured rabbit tracheal epithelial cells and B. bronchiseptica strains genetically locked in specific virulence states or expressing selective virulence genes will be used to model cell pathogenesis in initiating Bordetella sp. infection. Video microscopy will be used to assay changes in physical attachment, digital imaging microscopy to assay changes in host cell signaling an immunocytochemistry to assay changes in the host cell cytoskeleton associated with specific gene products produced by Bordetella sp. during cell pathogenesis. A greater understanding of bacterial/host interactions and their resulting physiological significance should lead to better development of prevention therapies and treatment strategies against bacterial invasion.