Transfer of eukaryotic expression plasmids to mammalian hosts by attenuated Salmonella spp

Transkingdom transfer of DNA from bacteria to other organisms, well established for bacteria, yeast and plants, was recently also extended to mammalian host cells. Attenuated intracellular bacteria or non-pathogenic bacteria equipped with adhesion and invasion properties have been demonstrated to transfer eukaryotic expression plasmids in vitro and in vivo. Here the mucosal application of attenuated Salmonella enterica spp. as DNA carrier for the induction of immune responses towards protein antigens encoded by expression plasmids, their use to complement genetic defects or deliver immunotherapeutic proteins is reviewed. Plasmid transfer has been reported for Salmonella typhimurium, S. typhi and S. choleraesuis so far but clearly other Salmonella strains should be able to transfer expression plasmids as well. Transfer of DNA is effected most likely by bacterial death within the host cell resulting from metabolic attenuation. Since these bacteria remain in the phagocytic vacuole it is unclear how the DNA from such dying bacteria is delivered to the nucleus of infected cells. Nevertheless, the efficiency that has been observed was astonishingly high, reaching close to 100% under certain conditions. Gene transfer in vivo was mainly directed towards vaccination strategies either as vaccination against infectious microorganisms or model tumors. Interestingly, in some cases tolerance against autologous antigens could be broken. In general, this type of immunization was more efficacious than either direct application of antigen, vaccination with naked DNA or using the same bacterium as a heterologous carrier expressing the antigen via a prokaryotic promoter. The ease of generating such vehicles for gene transfer combined with technology validated for mass vaccination programs and the efficacy of induction of protective immune responses makes Salmonella as carrier for mucosal DNA vaccination a highly attractive area for further research and development.