Optimization of a Type III Secretion System-Based Pseudomonas aeruginosa Live Vector for Antigen Delivery
| Autor: | Carole Margerit, Madiha Derouazi, Olivier Epaulard, Didier Filopon, Raphaël Marlu, Benoît Polack, Bertrand Toussaint |
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| Přispěvatelé: | Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), TheREx, VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Grants from the Association pour la Recherche contre le Cancer and from the Agence Nationale de la Recherche ('Emergence et Maturation de Projets de biotechnologie' BacVac 2007) |
| Rok vydání: | 2008 |
| Předmět: |
[SDV.BIO]Life Sciences [q-bio]/Biotechnology
medicine.medical_treatment Clinical Biochemistry Gene mutation MESH: Quorum Sensing Median lethal dose Mice Immunology and Allergy MESH: Animals [INFO.INFO-BT]Computer Science [cs]/Biotechnology 0303 health sciences biology Aroa Quorum Sensing Vaccine Research 3. Good health Bacterial vaccine Protein Transport Bacterial Vaccines Pseudomonas aeruginosa MESH: Pseudomonas aeruginosa Toxicity Female MESH: Genes Bacterial MESH: Dose-Response Relationship Immunologic Microbiology (medical) MESH: Protein Transport MESH: Cell Line Tumor Ovalbumin Virulence Factors Immunology Dose-Response Relationship Immunologic Vaccines Attenuated Microbiology Lethal Dose 50 03 medical and health sciences Antigen MESH: Mice Inbred C57BL Cell Line Tumor MESH: Vaccines Attenuated medicine Animals MESH: Mice MESH: Virulence Factors 030304 developmental biology MESH: Ovalbumin 030306 microbiology Lethal dose Immunotherapy biology.organism_classification Mice Inbred C57BL MESH: Lethal Dose 50 Genes Bacterial MESH: Gene Deletion MESH: Female Gene Deletion MESH: Bacterial Vaccines |
| Zdroj: | Clinical and Vaccine Immunology Clinical and Vaccine Immunology, American Society for Microbiology, 2008, 15 (2), pp.308-13. ⟨10.1128/CVI.00278-07⟩ |
| ISSN: | 1556-679X 1556-6811 |
| DOI: | 10.1128/cvi.00278-07 |
| Popis: | During the last few years, the use of type III secretion system-based bacterial vectors for immunotherapy purposes has been assessed in various applications. We showed that a type III secretion-based Pseudomonas aeruginosa vector delivering the ovalbumin (OVA) antigen induced an efficient specific CD8 + T-lymphocyte immune response against OVA-expressing cells. Because of the intrinsic toxicity of the vector, further virulence attenuation was needed. Therefore, we explored the effects of the deletion of quorum-sensing genes and the aroA gene toward toxicity and efficiency of the vector strain. The aroA mutation in our strain (making the strain auxotrophic for aromatic amino acids) conferred a strikingly reduced toxicity, with the bacterial lethal dose being more than 100 times higher than that of the parental strain. The quorum-sensing gene mutation alone was associated with a slightly reduced toxicity. In a prophylactic OVA-expressing melanoma mouse model, an OVA-delivering aroA -deficient mutant was the most efficient at a low dose (10 5 ), but dose enhancement was not associated with a greater immune response. The quorum-sensing-deficient strain was the most efficient at a mild dose (10 6 ), but this dose was close to the toxic dose. Combination of both mutations conferred the highest efficiency at an elevated dose (10 7 ), in agreement with the known negative effects of quorum-sensing molecules upon T-cell activation. In conclusion, we have obtained a promising immunotherapy vector regarding toxicity and efficiency for further developments in both antitumor and anti-infectious strategies. |
| Databáze: | OpenAIRE |
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