Yersinia pestis, the causative agent of plague, represents the most feared biological warfare agent, asindividuals infected via the respiratory route not only succumb to the disease within 72 hours, but alsotransmit Y. pestis to unexposed populations. Thus, the effect of a biological warfare attack with Y. pestis willbe amplified by the exponential spread of the resulting epidemic. Once an individual is infected with anaerosol of Y. pestis and once clinical signs become apparent, antibiotic therapy is no longer effective andvaccination of the general population appears to be the only effective means of prevention and protectionagainst plague. There is at present no effective commercially available plague vaccine. Protective immunityto Y. pestis infection can be achieved either by injecting live attenuated plague bacilli, killed bacterialsuspensions, or purified proteins ('protective antigens') into experimental animals. The latter cause minimalside effects and thus are preferred for immunization. Examples are the capsular antigen fraction 1 (Cafl)and the low-calcium-response protein V (LcrV or V antigen), however attempts to exploit Cafl and LcrV as asubunit vaccine may be futile. Major concerns are that the Cafl surface antigen is dispensable for thepathogenesis of Y. pestis infections and that LcrV is not only a suppressor of inflammation and immunity inhumans but also displays antigenic variation. These circumstances will either diminish the success of Cafl-LcrV vaccines or allow biological warfare organizations to generate plague strains capable of escapingimmune protection, thereby abrogating the defense effort of vaccine research. This proposal represents aninterdisciplinary and multi-institutional approach to develop new plague vaccines and to establish a rationalunderstanding of protective immunity against plague. Robert Brubaker (Michigan State University) and OlafSchneewind (University of Chicago) examine the pathogenesis of Y. pestis infections, the development ofplague vaccines and the Yersinia type III secretion mechanism. John Xu (University of Illinois, Urbana-Champaign) and Averil Ma (University of Chicago) study host immune functions that control Yersiniainfections and Natalia Maltsev (Argonne National Laboratory) applies bioinformatic approaches to theanalysis of Y. pestis genome sequences. This group of investigators will identify surface protein antigens ofY. pestis that are essential for the pathogenesis of plague.
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