Reducing the Activity and Secretion of Microbial Antioxidants Enhances the Immunogenicity of BCG
| العنوان: | Reducing the Activity and Secretion of Microbial Antioxidants Enhances the Immunogenicity of BCG |
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| المؤلفون: | Shanmugalakshmi Sadagopal, Douglas S. Kernodle, Miriam Braunstein, Louise Barnett, Markian R. Bochan, Spyros A. Kalams, Alexandria K. Daniel, Hiriam O. Gates, Luc Van Kaer, Ian Crozier, Cynthia C. Hager, James O. Price, Timothy S. Blackwell, Jie Wei, Nathaniel E. Smith |
| المصدر: | PLoS ONE PLoS ONE, Vol 4, Iss 5, p e5531 (2009) |
| بيانات النشر: | Public Library of Science, 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, T-Lymphocytes, lcsh:Medicine, Antioxidants, Infectious Diseases/Bacterial Infections, Mice, Immunology/Cellular Microbiology and Pathogenesis, lcsh:Science, Chemokine CCL5, 0303 health sciences, Mycobacterium bovis, Multidisciplinary, biology, Interleukin-12 Subunit p40, Immunogenicity, Public Health and Epidemiology/Global Health, 3. Good health, Microbiology/Immunity to Infections, medicine.anatomical_structure, BCG Vaccine, Tuberculosis vaccines, Microbiology/Cellular Microbiology and Pathogenesis, Meningitis, Research Article, Tuberculosis, Immunization, Secondary, Spleen, complex mixtures, Public Health and Epidemiology/Immunization, Mycobacterium tuberculosis, 03 medical and health sciences, Immune system, Adjuvants, Immunologic, Immunology/Immunity to Infections, medicine, Animals, RNA, Messenger, Tuberculosis, Pulmonary, 030304 developmental biology, 030306 microbiology, Interleukins, lcsh:R, biology.organism_classification, medicine.disease, Mice, Inbred C57BL, Oxidative Stress, Immunology, Interleukin-2, lcsh:Q |
| الوصف: | BACKGROUND:In early clinical studies, the live tuberculosis vaccine Mycobacterium bovis BCG exhibited 80% protective efficacy against pulmonary tuberculosis (TB). Although BCG still exhibits reliable protection against TB meningitis and miliary TB in early childhood it has become less reliable in protecting against pulmonary TB. During decades of in vitro cultivation BCG not only lost some genes due to deletions of regions of the chromosome but also underwent gene duplication and other mutations resulting in increased antioxidant production. METHODOLOGY/PRINCIPAL FINDINGS:To determine whether microbial antioxidants influence vaccine immunogenicity, we eliminated duplicated alleles encoding the oxidative stress sigma factor SigH in BCG Tice and reduced the activity and secretion of iron co-factored superoxide dismutase. We then used assays of gene expression and flow cytometry with intracellular cytokine staining to compare BCG-specific immune responses in mice after vaccination with BCG Tice or the modified BCG vaccine. Compared to BCG, the modified vaccine induced greater IL-12p40, RANTES, and IL-21 mRNA in the spleens of mice at three days post-immunization, more cytokine-producing CD8+ lymphocytes at the peak of the primary immune response, and more IL-2-producing CD4+ lymphocytes during the memory phase. The modified vaccine also induced stronger secondary CD4+ lymphocyte responses and greater clearance of challenge bacilli. CONCLUSIONS/SIGNIFICANCE:We conclude that antioxidants produced by BCG suppress host immune responses. These findings challenge the hypothesis that the failure of extensively cultivated BCG vaccines to prevent pulmonary tuberculosis is due to over-attenuation and suggest instead a new model in which BCG evolved to produce more immunity-suppressing antioxidants. By targeting these antioxidants it may be possible to restore BCG's ability to protect against pulmonary TB. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6045a0e822065091203da47c5a047959Test http://europepmc.org/articles/PMC2677452Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6045a0e822065091203da47c5a047959 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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