Bacillus Calmette-Guérin Overexpressing an Endogenous Stimulator of Interferon Genes Agonist Provides Enhanced Protection Against Pulmonary Tuberculosis

Ruchi Jain Dey, Bappaditya Dey, Alok Kumar Singh, Monali Praharaj, William Bishai

Research output: Contribution to journalArticle

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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)1048-1056
Number of pages9
JournalThe Journal of infectious diseases
Volume221
Issue number7
DOIs
StatePublished - Mar 16 2020

Keywords

  • CDNs
  • Calmette-Guérin (BCG)
  • Mycobacterium tuberculosis
  • STING
  • TB vaccine
  • c-di-AMP

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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