Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 221, Issue 7, Pages 1048-1056Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiz116
Keywords
Calmette-Guerin (BCG); c-di-AMP; CDNs; Mycobacterium tuberculosis; STING; TB vaccine
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Funding
- National Institutes of Health [AI37856, HL133190]
- Howard Hughes Medical Institute
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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. Methods. We generated a recombinant Bacillus Calmette-Guerin ([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. Results. BCG-disA-OE elicited significantly stronger tumor necrosis factor-alpha, interleukin (IL)-6, IL-1 beta, interferon (IFN) regulatory factor 3, and IFN-beta 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 log(10) CFU units (P < .05) compared with BCG-WT, respectively. 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.
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