Trained innate immunity and resistance to Mycobacterium tuberculosis infection

Some individuals, even when heavily exposed to an infectious tuberculosis patient, develop neither active nor latent tuberculosis infection (LTBI). This 'early clearance' of Mycobacterium tuberculosis is associated with a history of bacillus Calmette-Guérin (BCG) vaccination. As BCG vaccination can boost innate immune responses through a process termed 'trained immunity', we hypothesize that BCG-induced trained innate immunity contributes to early clearance of M. tuberculosis.

We describe the epidemiological evidence and biological concepts of early clearance and trained immunity, and the possible relation between these two processes through BCG vaccination.

Relevant data from published reports up to November 2018 were examined in the conduct of this review.

Several observational studies and one recent randomized trial support the concept that boosting innate immunity contributes to protection against M. tuberculosis infection, with BCG vaccination providing approximately 50% protection. The molecular mechanisms mediating early clearance remain largely unknown, but we propose that trained immunity, characterized by epigenetic and metabolic reprogramming of innate immune cells such as monocytes or macrophages, is at least partially responsible for eliminating the mycobacteria and inducing early clearance.

Future studies should examine if BCG revaccination increases early clearance of M. tuberculosis through induction of trained immunity. Epigenetic or metabolic modulation may further boost BCG-induced trained innate immunity to promote tuberculosis prevention. New tuberculosis vaccine candidates should also be examined for their capacity to improve protection against M. tuberculosis infection and induce trained immunity.