Targeting iron acquisition for prevention of disease in ruminants

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This study is focused on bacteria that colonize the upper respiratory tract of cattle and other ruminants and are the primary cause of respiratory infections, including ‘shipping fever’, which continues to be a major problem facing the cattle industry. Although there are a number of vaccines in use that are designed to prevent this infection, they have not substantially reduced the problem, primarily because they do not adequately deal with antigenic variation in the bacteria that cause the infection. To overcome this problem we plan to take advantage of a common trait that all these bacteria share, and ultimately develop improved vaccine antigens from the surface proteins that are common to these bacteria. The surface proteins that we propose to target are essential for acquiring iron for growth from the host iron binding protein, transferrin. Our first step is to determine the prevalence of these proteins in pathogens and related bacteria that colonize the upper respiratory tract and to obtain a detailed understanding of antigenic diversity of these proteins. The reason this is important is that if the proteins are present in other bacteria that colonize the upper respiratory tract, they may serve as a reservoir for antigenic variants that the pathogens could use to evade the vaccine. Comparison of the sequences of these proteins will be enhanced by the availability of the detailed three-dimensional structure of several of these proteins that our group has determined. The detailed understanding of the location and function of the variable regions of these proteins will provide the foundation for structure-based protein engineering for developing antigens with improved immunological properties. We also plan to use novel assays we developed to evaluate sera from immunized animals for their ability to protect against strains carrying the diverse set antigenic variants of the proteins. These assays will be useful for engineering improved and optimized vaccine antigens, and will provide a relatively inexpensive means of evaluating how cross-protective vaccines will be.