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Bacillus Calmette-Guérin Overexpressing an Endogenous Stimulator of Interferon Genes Agonist Provides Enhanced Protection Against Pulmonary Tuberculosis.
- Source :
-
The Journal of infectious diseases [J Infect Dis] 2020 Mar 16; Vol. 221 (7), pp. 1048-1056. - Publication Year :
- 2020
-
Abstract
- Background: Stimulator of interferon genes (STING) is a key cytosolic receptor for small nucleotides and plays a key role in anticancer and antiviral immunity. Cyclic dinucleotide STING agonists may comprise a novel class of vaccine adjuvants capable of inducing cellular immune responses and protective efficacy against intracellular pathogens.<br />Methods: We generated a recombinant Bacillus Calmette-Guérin ([BCG] BCG-disA-OE) that overexpresses the endogenous mycobacterial diadenylate cyclase gene and releases high levels of the STING agonist bis-(3'-5')-cyclic dimeric adenosine monophosphate (c-di-AMP). We used a 24-week guinea pig vaccination-Mycobacterium tuberculosis (M.tb.) challenge model to test the protective efficacy of BCG-disA-OE versus wild-type BCG and measured lung weights, pathology scores, and M.tb. organ colony-forming unit (CFU) counts.<br />Results: BCG-disA-OE elicited significantly stronger tumor necrosis factor-α, interleukin (IL)-6, IL-1β, interferon (IFN) regulatory factor 3, and IFN-β levels than BCG-wild type (WT) in vitro in murine macrophages. In vivo in guinea pigs, we found that BCG-disA-OE reduced lung weights, pathology scores, and M.tb. CFU counts in lungs by 28% (P < .05), 34%, and 2.0 log10 CFU units (P < .05) compared with BCG-WT, respectively.<br />Conclusions: We report a strategy of delivering a STING agonist from within live BCG. Overproduction of the STING agonist c-di-AMP significantly enhanced the protective efficacy of BCG against pulmonary and extrapulmonary tuberculosis. Our findings support the development of BCG-vectored STING agonists as a tuberculosis vaccine strategy.<br /> (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Subjects :
- Animals
Cells, Cultured
Cytokines metabolism
Female
Guinea Pigs
Lung drug effects
Lung metabolism
Lung pathology
Macrophages drug effects
Macrophages microbiology
Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Mycobacterium tuberculosis drug effects
BCG Vaccine chemistry
BCG Vaccine pharmacology
Dinucleoside Phosphates pharmacology
Membrane Proteins agonists
Tuberculosis, Pulmonary metabolism
Tuberculosis, Pulmonary pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6613
- Volume :
- 221
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 30901058
- Full Text :
- https://doi.org/10.1093/infdis/jiz116