Francisella tularensis is a highly infectious bacterium that poses a serious threat as an agent ofbioterrorism.A live whole cell vaccine is currently available for at-risk populations, but it is associated with incompleteimmunity and side-effects. Studies of humans and mice vaccinated with this preparation indicate thathumoral and cell-mediated immune responses are required for complete protection in the infected host.Currently, little is known concerning the virulence factors associated with F. tularensis that contribute to itsability to cause lethal disease. However, previous studies have identified the capsule and LPS as principledeterminants of its pathogenic potential. Our analysis of the recently released genome ofF. tularensis Schu$4 has shown that it possesses a single polysaccharide biosynthetic locus responsible for expression of onesurface polysaccharide. Based on these data, we hypothesize that the previously described capsule andO-antigen of this organism actually represents a single O-antigen/capsule that has the same repeatingunit structure, but is expressed as a distinct large molecular-weight polymer and smaller molecularweightLipid A-linked polysaccharide. We predict that this structure has a central role in thepathogenesis of this organism and can be used as the basis for novel glycoconjugate vaccines that willelicit complete protection against experimental tularemia. To address the structural nature of thisvirulence factor and its role in the pathogenesis and immunity to F. tularensis, we propose to: 1) Characterizethe structural and genetic nature of the O-antigen/capsule; 2) Determine the role of the O-antigen/capsule invirulence; 3) Determine the humoral and cell-mediated immune responses to the O-antigen/capsule andproteins ofF. tularensis; and 4) Develop a conjugate vaccine for F. tularensis infections. These studies willemploy a proteomics-based approach to identify new immunogenic proteins from F. tularensis that can beused as carriers in the development of novel acellular glycoconjugate vaccines. It is anticipated that thesevaccines will activate both humoral and cell-mediated immune responses and elicit complete protectionagainst tularemia. Glycoconjugate vaccines have been among the most effective biologics ever developedfor the prevention of bacterial infections. It is expected that this approach can be applied successfully to thedevelopment of a vaccine that can ultimately be tested in clinical trials for the prevention of tularemia.
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