Protection Against Murine Listeriosis by Oral Vaccination with Recombinant <i>Salmonella</i> Expressing Hybrid <i>Yersinia</i> Type III Proteins

Rüssmann, Holger; Igwe, Emeka I.; Sauer, Jeannette; Hardt, Wolf‐Dietrich; Bubert, Andreas; Geginat, Gernot

doi:10.4049/jimmunol.167.1.357

Cited by 78 publications

(84 citation statements)

References 57 publications

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“…This indicates that N-terminal residues of IpaH9.8 can be used as a signal sequence to allow secretion of foreign proteins by Shigella. Furthermore, our data are consistent with the finding that N-terminal residues from YopE of Yersinia can be successfully recognized by a heterologous type III secretion system (25,27).…”

Section: Discussionsupporting

confidence: 81%

Delivery of Biologically Active Anti-Inflammatory Cytokines IL-10 and IL-1ra In Vivo by the Shigella Type III Secretion Apparatus

Chamekh

Phalipon

Quertainmont

et al. 2008

The Journal of Immunology

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Pathogenicity of many Gram-negative bacteria relies on a type III secretion (T3S) apparatus, which is used for delivery of bacterial effectors into the host cell cytoplasm allowing the bacteria to manipulate host cell cytoskeleton network as well as to interfere with intracellular signaling pathways. In this study, we investigated the potential of the Shigella flexneri T3SA as an in vivo delivery system for biologically active molecules such as cytokines. The anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist (IL-1ra) were genetically fused to the first 30 or 60 residues of the Shigella T3S effector IpaH9.8 or to the first 50 residues of the Yersinia enterocolitica effector YopE and the recombinant fusion proteins were expressed in S. flexneri. YopE50-IL-10, IpaH60-IL-10, and IpaH60-IL-1ra were efficiently secreted via the T3S apparatus of Shigella. Moreover, these recombinant proteins did not impair the invasive ability of the bacteria in vitro. In a murine model, Shigella strains expressing YopE50-IL-10, IpaH60-IL-10, and IpaH60-IL-1ra induced a lower mortality in mice that was associated with reduced inflammation and a restricted localization of bacteria within the lung tissues as compared with wild-type Shigella. Moreover, the level of TNF-α and IL-1β mRNA were reduced in the lungs following infection by IL-10- and IL-1ra-secreting Shigella, respectively. These findings demonstrate that the Shigella T3S apparatus can deliver biologically active cytokines in vivo, thus opening new avenues for the use of attenuated bacteria to deliver proteins for immunomodulation or gene therapy purposes.

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Section: Discussionsupporting

confidence: 81%

Delivery of Biologically Active Anti-Inflammatory Cytokines IL-10 and IL-1ra In Vivo by the Shigella Type III Secretion Apparatus

Chamekh

Phalipon

Quertainmont

et al. 2008

The Journal of Immunology

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“…Recombinant fusion proteins have been reported to be effective in the development of oral vaccines (20,21). However, this is the first demonstration, to our knowledge, that Tf moiety in Tf-based recombinant technology enhances the GI absorption of a therapeutic protein drug.…”

Section: Discussionmentioning

confidence: 91%

Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent

Bai

Ann

Shen

2005

Proc. Natl. Acad. Sci. U.S.A.

116

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An expression construct harboring granulocyte colony-stimulating factor (G-CSF)-transferrin (Tf) fusion protein (G-CSF-Tf) was engineered by fusing human cDNAs encoding G-CSF and Tf to explore the feasibility of using Tf as a carrier moiety for oral delivery of therapeutic proteins. The recombinant protein, G-CSF-Tf, was harvested from protein-free, conditioned medium of transfected HEK293 cells. The in vitro studies demonstrated that the purified G-CSF-Tf fusion protein possesses the activity of both Tf receptor (TfR) binding in Caco-2 cells and G-CSF-dependent stimulation of NFS-60 cell proliferation. Subcutaneous administration of G-CSF-Tf fusion protein to BDF1 mice demonstrated a pharmacological effect comparable to the commercial G-CSF on the increase of absolute neutrophil counts (ANC). However, the fusion protein elicited a significant increase in ANC upon oral administration to BDF1 mice, whereas G-CSF had no effect. This study also showed that orally administered G-CSF-Tf elicits a sustained myelopoietic effect up to 3 days, whereas the s.c. administered G-CSF or G-CSF-Tf lasts only 1 day. Furthermore, coadministration of free Tf abolished the increase of ANC by orally delivered G-CSF-Tf, suggesting that the recombinant protein is absorbed via a TfR-mediated process in the gastrointestinal tract. Taken together, we conclude that the Tf-based recombinant fusion protein technology represents a promising approach for future development of orally effective peptide and protein drugs. myelopoiesis ͉ oral delivery ͉ protein drug

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“…These comparable low doses of oridonin and As 2 O 3 have been used in previous combination therapy studies (25,26). Consistence with the synergistic pro-apoptosis effect in vitro, the two-drug combination displayed significantly enhanced antitumor activity compared with that induced by oridonin or As 2 O 3 alone (Fig.…”

Section: Enhanced Antitumor Activity In Vivo Of the Two-drug Combinatmentioning

confidence: 99%

Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular carcinoma cells

Hua¹

2011

Int J Oncol

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Abstract. Although arsenic trioxide (As 2 O 3 ) has been successfully employed in treatment of patients with APL (acute promyelocytic leukemia), the sensitivity of solid tumor cells to this treatment was much lower than APL cells. The single agent of As 2 O 3 was inefficient for treatment of hepatocellular carcinoma (HCC) in phase II trial demonstrating that new modalities of treatment with enhanced therapeutic effect are needed. In this study, we showed that oridonin, a diterpenoid isolated from traditional Chinese medicine Rabdosia rubescences, greatly potentiated apoptosis induced by As 2 O 3 in hepatocellular carcinoma cells. The synergistic pro-apoptosis effect of combination of these two drugs led to increase in intracellular reactive oxygen species (ROS) level and N-acetyl-L-cysteine (NAC), a thiolcontaining anti-oxidant, was able to completely block the effect. The combination treatment induced ROS-dependent decrease in mitochondrial membrane potential (MMP) decrease, and relocation of Bax and cytochrome C. Besides, oridonin dramatically increased the intracellular Ca 2+ overload triggered by As 2 O 3 . Furthermore, the co-treatment of oridonin and As 2 O 3 induced ROS-mediated down-regulation of Akt and XIAP, and inhibition of NF-κB activation. The two drug combination enhanced tumor suppression activity in murine HCC model compared with single agent treatment in vivo. These findings demonstrate that oridonin can sensitize hepatocellular carcinoma cells to As 2 O 3 treatment and will facilitate the optimization of As 2 O 3 therapy for HCC patients.

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Protection Against Murine Listeriosis by Oral Vaccination with Recombinant Salmonella Expressing Hybrid Yersinia Type III Proteins

Cited by 78 publications

References 57 publications

Delivery of Biologically Active Anti-Inflammatory Cytokines IL-10 and IL-1ra In Vivo by the Shigella Type III Secretion Apparatus

Delivery of Biologically Active Anti-Inflammatory Cytokines IL-10 and IL-1ra In Vivo by the Shigella Type III Secretion Apparatus

Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent

Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular carcinoma cells

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