Targeting T3SA proteins as protective antigens against Yersinia

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Summary Yersinia pestis causes bubonic, septicemic and pneumonic plague with high rates of mortality in the absence of immediate treatment. Although Y. pestis is susceptible to many antibiotics and outbreaks have been contained in present day, plague continues to cause lethal human infections in areas where Y. pestis has established persistent enzootic cycles in wild rodents. In 2015, 15 plague cases were reported in the United States, several occurring in National Parks, with a case fatality rate of ~33%. This underscores the challenges associated with combatting this devastating disease. Additionally, Y. pestis has been deployed as a biological weapon and with its genetic tractability, natural acquisition of antibiotic resistance and relative ease of acquisition from nature, Y. pestis has been classified as a weaponizable pathogen with the potential for inflicting widespread human death. Yersinia spp. that are pathogenic for humans possess a type III secretion system (T3SS) that is essential for virulence. This T3SS injects protein effectors into host cells to manipulate functions for the benefit of the bacterium. The T3SS apparatus (T3SA) provides the energized conduit for translocation of these effectors from the bacterium and into the host cell cytoplasm. The external portions of the T3SA are the needle, the tip protein and the first of two translocator proteins. For Yersinia, LcrV is the needle tip protein and YopB is the first translocator protein. These proteins are highly conserved among Yersinia spp. and are required for pathogenesis. We have demonstrated that, when administered intranasally (IN) in the presence of the appropriate adjuvant, these two proteins protect mice against a lethal challenge by Y. pestis and Y. enterocolitica. We have fused LcrV and YopB to produce YerF and have fused LTA1, the active moiety of dmLT (double mutant labile toxin) from enterotoxigenic E. coli, to the N-terminus of these fusions to produce L-YerF. Within this proposal, we intend to assess the L-YerF as a self- adjuvanting protective subunit vaccine. We hypothesize that L-YerF will provide humoral and cellular immune responses that will protect mice against infections causing pneumonic and bubonic plague.