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

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

doi:10.1093/infdis/jiz116

Ruchi Jain Dey, Alok Kumar Singh + Show 3 more

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https://doi.org/10.1093/infdis/jiz116

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Abstract

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. 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. 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. 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.

Highlights

Recent studies have identified a key role for the stimulator of interferon genes (STING) intracellular sensor in mediating innate immune responses cellular stress or pathogen infection [1,2]
As they are capable of inducing potent cytokine and cellular immune responses against pathogens, cyclic dinucleotides (CDNs) Stimulator of interferon genes (STING) agonists exhibit attractive vaccine adjuvant properties
We showed that mutation of the cdnP gene encoding a cyclic dinucleotide phosphodiesterase (CdnP) that hydrolyzes c-di-AMP lead to a mutant Mycobacterium tuberculosis (Mtb) strain that accumulates c-di-AMP and is attenuated for virulence [13]

Summary

Introduction

Recent studies have identified a key role for the stimulator of interferon genes (STING) intracellular sensor in mediating innate immune responses cellular stress or pathogen infection [1,2]. STING agonists is currently being tested for enhancement of antitumor immunity and as potential anti-viral therapy [5,7]. As they are capable of inducing potent cytokine and cellular immune responses against pathogens, CDN STING agonists exhibit attractive vaccine adjuvant properties. They increase expression of MHC class II, co-stimulatory molecules (CD80/CD86) as well as activation (CD40) and adhesion (CD45) markers; in addition

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