A Modified Bacillus Calmette-Guérin (BCG) Vaccine with Reduced Activity of Antioxidants and Glutamine Synthetase Exhibits Enhanced Protection of Mice despite Diminished in Vivo Persistence
Abstract
:1. Introduction
2. Results and Discussion
2.1. Construction of 4dBCG
2.2. 4dBCG Is Cleared More Rapidly than BCG from the Spleens of Mice
2.3. Vaccination with 4dBCG Exhibits Greater Protection than BCG against Early Dissemination of Aerosolized M. tuberculosis to the Spleen
2.4. Vaccination with 4dBCG Alters the Pattern of Lymphohistiocytic Infiltration of Lung Parenchyma at 8 Weeks Post-Challenge
2.5. Vaccination with 4dBCG Reduces Lung Cfu Counts at 26 Weeks Post-Challenge
2.6. Advantages and Limitations of This Vaccine Strategy and Its Implications for Human Vaccination
3. Experimental
3.1. Bacterial Isolates, Plasmids, Antibiotics, and Media
Name | Description | Reference or source |
---|---|---|
Plasmids | ||
pCR2.1-TOPO | Plasmid for cloning PCR products | Invitrogen Corp., Carlsbad, California |
pBC SK+ | E. coli phagemid vector | Stratagene, La Jolla, CA |
pHV203 | E. coli-mycobacterial shuttle plasmid with kanamycin resistance gene | [16] |
pHV203-dnglnA1-ΔD54ΔE335 | pHV203 with ΔD54ΔE335 dn mutant glnA1 gene with its own promoter | This study |
Strains | ||
Erdman S-1 | M. tuberculosis WHO Standard lot 1 (Mtb S-1) prepared from virulent Erdman lot K01 from the Trudeau Institute and filled by Mycos Research, Loveland, CO | Amy Yang, FDA, Bethesda, MD [64] |
TOP 10 | Host strain for cloning PCR products, used in combination with pCR2.1-TOPO | Invitrogen Corp., Carlsbad, California |
DH5α | E. coli host strain for genetic manipulation, construction of mutant enzyme expression vectors | Life Technologies, Gaithersburg, MD [87] |
BCG Tice | Bacillus Calmette-Guérin, substrain Tice | Organon Teknika Corp., Durham, NC [82,83] |
3rd generation modified BCG vaccine (three modifications) | ||
3dBCG | BCG Tice with inactivated sigH and secA2 containing the chromosomal integration vector pMP399-dnsodA-ΔH28ΔH76 | [12] |
4th generation modified BCG vaccine (four modifications) | ||
4dBCG | BCG Tice with inactivated sigH and secA2 containing pMP399-dnsodA-ΔH28ΔH76 and pHV203-dnglnA1-ΔD54ΔE335 | This study |
3.2. Molecular Genetic Manipulations
3.3. Expression of Mutant Enzyme Alleles in BCG and Assays of Enzyme Activity
3.4. Animal Procedures
3.5. Histopathology
3.6. Statistical Comparisons
4. Conclusions
Conflict of Interests
Acknowledgments
References
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Shoen, C.M.; DeStefano, M.S.; Hager, C.C.; Tham, K.-T.; Braunstein, M.; Allen, A.D.; Gates, H.O.; Cynamon, M.H.; Kernodle, D.S. A Modified Bacillus Calmette-Guérin (BCG) Vaccine with Reduced Activity of Antioxidants and Glutamine Synthetase Exhibits Enhanced Protection of Mice despite Diminished in Vivo Persistence. Vaccines 2013, 1, 34-57. https://doi.org/10.3390/vaccines1010034
Shoen CM, DeStefano MS, Hager CC, Tham K-T, Braunstein M, Allen AD, Gates HO, Cynamon MH, Kernodle DS. A Modified Bacillus Calmette-Guérin (BCG) Vaccine with Reduced Activity of Antioxidants and Glutamine Synthetase Exhibits Enhanced Protection of Mice despite Diminished in Vivo Persistence. Vaccines. 2013; 1(1):34-57. https://doi.org/10.3390/vaccines1010034
Chicago/Turabian StyleShoen, Carolyn M., Michelle S. DeStefano, Cynthia C. Hager, Kyi-Toe Tham, Miriam Braunstein, Alexandria D. Allen, Hiriam O. Gates, Michael H. Cynamon, and Douglas S. Kernodle. 2013. "A Modified Bacillus Calmette-Guérin (BCG) Vaccine with Reduced Activity of Antioxidants and Glutamine Synthetase Exhibits Enhanced Protection of Mice despite Diminished in Vivo Persistence" Vaccines 1, no. 1: 34-57. https://doi.org/10.3390/vaccines1010034