The elucidation of the oral/respiratory axis in inducing protective immunity against Francisella tularensis (161.22)

Abstract

Abstract Using a Francisella tularensis subspecies novicida live attenuated vaccine strain (U112ΔiglB), we have shown that oral vaccination of C57BL/6 mice induces significant protective immunity against pulmonary challenge with the highly human virulent F. tularensis strain SCHU S4. This protection is primarily mediated by antigen-specific CD4+ T cells and IFN-γ production and is dependent on mucosal IgA expression. We are examining the mechanism(s) by which the oral/respiratory axis induces optimal protective immunity against F. tularensis. Intestinal M-cells play an important role in oral vaccination by trafficking antigens from the lumen to the lamina propria and in presentation of antigens to underlying APCs for the subsequent induction of mucosal immunity. We have shown that mCherry-labeled U112ΔiglB co-localizes to intestinal mouse M-cells by 90 minutes following vaccination. Localization to M-cells was further verified with mouse ileal loops. Translocation of U112ΔiglB has also been demonstrated through M-cell-like-cells in an in vitro transwell co-culture system similar to M-cell trophic enteric bacteria. Current studies are examining the functional importance of intestinal M-cells in induction of mucosal immunity for the rational development of an effective oral vaccine against pulmonary tularemia. These studies will provide information for the general design of oral vaccines using live attenuated bacterial strains.