Function and immunogenicity of Yersinia pestis fimbriae

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DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of Plague. Aerosolized Y. pestis is feared as a most dangerous bioweapon. There is currently no vaccine protecting humans against pneumonic Plague, the most contagious and lethal form of Plague. The long-term goal of this project is to develop a new, cost-effective vaccine capable of inducing mucosal and systemic immunity for extended protection against Plague. The studied major prototype vaccines against Y. pestis are based on only two subunit antigens, one not required for virulence. Such vaccines might not protect a sufficiently broad population of individuals with different genetic backgrounds. They also run the risk of becoming ineffective against naturally selected or engineered mutants of Y. pestis. The recently deciphered Y. pestis genome will be used to study additional immunogenic protein targets, preferably involved in some aspects of Y. pestis pathogenesis. The fimbrial proteins found in most if not all Enterobacteriaceae, including Y. pestis, are bestowed with such properties. Fimbriae are polymeric proteins assembled as hair-like organelles on bacterial surfaces. In addition to being among the best studied and most effective bacterial immunogens, many fimbriae are directly involved in mediating bacterial binding to host mucosal surfaces. Fimbriae induce typically high titers of both anti-bacterial and antiadhesive antibodies. They can be isolated in large amounts by simple methods, making them cost-effective vaccines. The first aim of this project is to clone each of the identified fimbrial gene clusters and to express the fimbriae on the surface of E. coli. Second, we will determine whether any of these fimbriae mediate E. coil binding to relevant epithelial cells or cells of the innate immune system. Third, in vivo expression of fimbriae will be determined by screening for antibodies in challenged mice. The importance of the fimbriae in pathogenesis will be studied with mutants. Fourth, mice will be immunized parenterally with fimbriae, and either orally or intra-nasally with an attenuated Salmonella vaccine strain expressing Y. pestis fimbriae. Systemic and mucosal humoral immune responses and the elicitation of anti-adhesive antibodies will be investigated. Challenge experiments will be undertaken to study immuno-protection by these vaccines.