Attenuated Shigella as a DNA Delivery Vehicle for DNA-Mediated Immunization

Abstract

Direct inoculation of DNA, in the form of purified bacterial plasmids that are unable to replicate in mammalian cells but are able to direct cell synthesis of foreign proteins, is being explored as an approach to vaccine development. Here, a highly attenuated Shigella vector invaded mammalian cells and delivered such plasmids into the cytoplasm of cells, and subsequent production of functional foreign protein was measured. Because this Shigella vector was designed to deliver DNA to colonic mucosa, the method is a potential basis for oral and other mucosal DNA immunization and gene therapy strategies.

In vivo correction of genetic defects of monocyte/ macrophages using attenuated Salmonella as oral vectors for targeted gene delivery

“…[1][2][3] It has been shown that bacteria, which have evolved the ability to enter mammalian cells, are able to transfer genetic material to host cells without major DNA rearrangements occurring during the transkingdom transfer process. [4][5][6] Attenuated Salmonella strains have been successfully used as a carrier system for the in vivo delivery of nucleic acid-based vaccines. 7 This approach has proven to be efficacious in protecting against infectious diseases and for cancer immunotherapy.…”

Engineered E. coli delivers therapeutic genes to the colonic mucosa

“…Attenuated mutant strains of Shigella flexneri, Salmonella typhimurium as well as invasive E. coli and L. monocytogenes can successfully transfer in vitro plasmid DNA to a wide range of rodents and primate cell lines as well as dendritic cells. [12][13][14][15][16] So far, the ability of Shigella and Salmonella to target dendritic cells has been mainly exploited to develop DNA vaccines. 12,15,32 However, more recently, invasive bacteria have been used also as DNA vectors to correct inherited genetic defects in somatic cells.…”

“…[12][13][14][15][16] So far, the ability of Shigella and Salmonella to target dendritic cells has been mainly exploited to develop DNA vaccines. 12,15,32 However, more recently, invasive bacteria have been used also as DNA vectors to correct inherited genetic defects in somatic cells. Administration to genetically immunodeficient mice of avirulent Salmonella bearing murine IFN-g gene resulted in transgene expression within macrophages and dendritic cells, correction of the genetic defect, and restoration of the cellular phenotype.…”

“…8,9 Several laboratories have recently demonstrated that bacteria can transfer functional genes to a very broad range of eukaryotic cells. 10,11 Attenuated strains of Shigella, 12 invasive Escherichia coli, 13,14 Salmonella, 15 and Listeria 16 are able to transfer plasmid DNA to mammalian cells. The bacteria used to transfer genes to phagocytic and nonphagocytic cells are facultative intracellular pathogens that have been designed to lyse after cell invasion.…”

Mucosal delivery of vaccines in domestic animals

“…However, one of the major concerns regarding the use of bacterial vectors particularly those derived from attenuated strains is the stability of the recombinant phenotype and the potential reversion to full virulence [101]. In addition, although a number of bacterial vectors [34,37,93,133,147,148,151]. Although significant progress has been made in developing and evaluating bacterial vectors for inducing protective immune responses, there are not many reports of their application to vaccinate veterinary species (Tab.…”