Dataset Information

A Salmonella Typhimurium mutant strain capable of RNAi delivery: higher tumor-targeting and lower toxicity.

ABSTRACT: Bacteria are highly versatile and useful tools that could deliver short interfering RNA. In this study, a phoP/phoQ double-deleted Salmonella Typhimurium named VNP(PhoP/Q(-)) based on the genetic background of VNP20009. The biological safety and function of VNP(PhoP/Q(-)) were also analyzed. Our study revealed the following results: (1) VNP(PhoP/Q(-)) exhibited lower titers in tumor-free livers and spleens than VNP20009, (2) The survival of VNP(PhoP/Q(-)) in macrophages and 4T1 tumor cells was significantly reduced compared with that of VNP20009, (3) The tumor-targeting ability of VNP(PhoP/Q(-)) was significantly enhanced compared with that of VNP20009, and the anticancer effects of VNP(pPhoP/Q(-)) and VNP20009 on tumor-bearing mice were similar, (4) VNP(PhoP/Q(-)) could release an shRNA-expressing plasmid and express the EGFP reporter gene in tumor tissue. Therefore, VNP(PhoP/Q(-)) exhibited a better safety level in tumor-free mice and elicited an anti-tumor effect on tumor-bearing mice. Moreover, VNP(PhoP/Q(-)) could release an shRNA-expressing plasmid into the cytoplasm of host cells to silence targeted genes.

SUBMITTER: Cheng X

PROVIDER: S-EPMC4119074 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Salmonella Typhimurium mutant strain capable of RNAi delivery: higher tumor-targeting and lower toxicity.

Cheng Xiawei X Zhang Xiaoxin X Zhou Yuqiang Y Zhang Chunmei C Hua Zi-Chun ZC

Cancer biology & therapy 20140519 8

Bacteria are highly versatile and useful tools that could deliver short interfering RNA. In this study, a phoP/phoQ double-deleted Salmonella Typhimurium named VNP(PhoP/Q(-)) based on the genetic background of VNP20009. The biological safety and function of VNP(PhoP/Q(-)) were also analyzed. Our study revealed the following results: (1) VNP(PhoP/Q(-)) exhibited lower titers in tumor-free livers and spleens than VNP20009, (2) The survival of VNP(PhoP/Q(-)) in macrophages and 4T1 tumor cells was s ...[more]

PMID: 24842165

Similar Datasets

Project description:Recombinant attenuated Salmonella enterica serovar Typhimurium strains are believed to act as powerful live vaccine carriers that are able to elicit protection against various pathogens. Auxotrophic mutations, such as a deletion of aroA, are commonly introduced into such bacteria for attenuation without incapacitating immunostimulation. In this study, we describe the surprising finding that deletion of aroA dramatically increased the virulence of attenuated Salmonella in mouse models. Mutant bacteria lacking aroA elicited increased levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) after systemic application. A detailed genetic and phenotypic characterization in combination with transcriptomic and metabolic profiling demonstrated that ΔaroA mutants display pleiotropic alterations in cellular physiology and lipid and amino acid metabolism, as well as increased sensitivity to penicillin, complement, and phagocytic uptake. In concert with other immunomodulating mutations, deletion of aroA affected flagellin phase variation and gene expression of the virulence-associated genes arnT and ansB Finally, ΔaroA strains displayed significantly improved tumor therapeutic activity. These results highlight the importance of a functional shikimate pathway to control homeostatic bacterial physiology. They further highlight the great potential of ΔaroA-attenuated Salmonella for the development of vaccines and cancer therapies with important implications for host-pathogen interactions and translational medicine. Recombinant attenuated bacterial vector systems based on genetically engineered Salmonella have been developed as highly potent vaccines. Due to the pathogenic properties of Salmonella, efficient attenuation is required for clinical applications. Since the hallmark study by Hoiseth and Stocker in 1981 (S. K. Hoiseth and B. A. D. Stocker, Nature 291:238-239, 1981, http://dx.doi.org/10.1038/291238a0), the auxotrophic ΔaroA mutation has been generally considered safe and universally used to attenuate bacterial strains. Here, we are presenting the remarkable finding that a deletion of aroA leads to pronounced alterations of gene expression, metabolism, and cellular physiology, which resulted in increased immunogenicity, virulence, and adjuvant potential of Salmonella. These results suggest that the enhanced immunogenicity of aroA-deficient Salmonella strains might be advantageous for optimizing bacterial vaccine carriers and immunotherapy. Accordingly, we demonstrate a superior performance of ΔaroA Salmonella in bacterium-mediated tumor therapy. In addition, the present study highlights the importance of a functional shikimate pathway to sustain bacterial physiology and metabolism.

Dataset Information

A Salmonella Typhimurium mutant strain capable of RNAi delivery: higher tumor-targeting and lower toxicity.

Publications

A Salmonella Typhimurium mutant strain capable of RNAi delivery: higher tumor-targeting and lower toxicity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets