The immunogenic potential of bacterial flagella for Salmonella-mediated tumor therapy.
Administration, Intravenous
Animals
Bacterial Proteins
/ genetics
Cell Line, Tumor
Colonic Neoplasms
/ immunology
Disease Models, Animal
Flagella
/ genetics
Membrane Proteins
/ genetics
Mice
Microscopy, Electron, Scanning
Mutation
Proton-Translocating ATPases
/ genetics
RAW 264.7 Cells
Salmonella typhimurium
/ genetics
Treatment Outcome
Xenograft Model Antitumor Assays
Salmonella typhimurium
bacteria-mediated tumor therapy
flagella
host-pathogen interaction
luminex
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 07 2020
15 07 2020
Historique:
received:
20
08
2019
revised:
07
11
2019
accepted:
12
11
2019
pubmed:
23
11
2019
medline:
9
3
2021
entrez:
23
11
2019
Statut:
ppublish
Résumé
Genetically engineered Salmonella Typhimurium are potent vectors for prophylactic and therapeutic measures against pathogens as well as cancer. This is based on the potent adjuvanticity that supports strong immune responses. The physiology of Salmonella is well understood. It simplifies engineering of both enhanced immune-stimulatory properties as well as safety features, thus, resulting in an appropriate balance between attenuation and efficacy for clinical applications. A major virulence factor of Salmonella is the flagellum. It is also a strong pathogen-associated molecular pattern recognized by extracellular and intracellular receptors of immune cells of the host. At the same time, it represents a serious metabolic burden. Accordingly, the bacteria evolved tight regulatory mechanisms that control flagella synthesis in vivo. Here, we systematically investigated the immunogenicity and adjuvant properties of various flagella mutants of Salmonella in vitro and in a mouse cancer model in vivo. We found that mutants lacking the flagellum-specific ATPase FliHIJ or the inner membrane ring FliF displayed the greatest stimulatory capacity and strongest antitumor effects, while remaining safe in vivo. Scanning electron microscopy revealed the presence of outer membrane vesicles in the ΔfliF and ΔfliHIJ mutants. Finally, the combination of the ΔfliF and ΔfliHIJ mutations with our previously described attenuated and immunogenic background strain SF102 displayed strong efficacy against the highly resistant cancer cell line RenCa. We thus conclude that manipulating flagella biosynthesis has great potential for the construction of highly efficacious and versatile Salmonella vector strains.
Substances chimiques
Bacterial Proteins
0
Flif protein, Bacteria
0
Membrane Proteins
0
fliH protein, Bacteria
138414-67-2
fliI protein, bacteria
138414-68-3
fliJ protein, Bacteria
138414-69-4
Proton-Translocating ATPases
EC 3.6.3.14
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
448-460Informations de copyright
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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