Reversing BCG-mediated autophagy inhibition and mycobacterial survival to improve vaccine efficacy

Background: Autophagy is an important mechanism for promoting Mycobacterium clearance from macrophages. Pathogenic and non-pathogenic mycobacterium can activate the mTOR pathway while simultaneously inducing autophagy. M. tuberculosis and M. bovis BCG inhibit autophagy and favor intracellular bacteria survival. Results: We observed that pre-infection of live or heat-killed BCG could prevent autophagy induced by pharmacological activators or M. smegmatis, a strong autophagy-inducing mycobacterium. BCG-derived lipids are responsible for autophagy inhibition. However, post-infection with BCG could not stop the autophagy initiated by M. smegmatis, which increases further autophagy induction and mycobacteria clearance. Coinfection with BCG and heat killed M. smegmatis enhanced antigen specific CD4⁺ T cell responses and reduced mycobacterial survival. Conclusion: These results suggest that autophagy-inducing M. smegmatis could be used to promote better innate and consequential adaptive immune responses, improving BCG vaccine efficacy.