Heat-killed <i>Mycobacterium tuberculosis</i> induces trained immunity <i>in vitro</i> and <i>in vivo</i> administered systemically or intranasally

Trained immunity (TI) represents a memory-like process of innate immune cells. TI can be initiated with various compounds such as fungal β-glucan or the tuberculosis vaccine, Bacillus Calmette-Guérin. Nevertheless, considering the clinical applications of harnessing TI against infections and cancer, there is a growing need for new, simple, and easy-to-use TI inducers. Here, we demonstrate that heat-killed Mycobacterium tuberculosis (HK Mtb ) induces TI both in vitro and in vivo . In human monocytes, this effect represents a truly trained process, as HK Mtb confers boosted inflammatory responses against various heterologous challenges, such as lipopolysaccharide (Toll-like receptor [TLR] 4 ligand) and R848 (TLR7/8 ligand). Mechanistically, HK Mtb -induced TI relies on epigenetic mechanisms in a Syk/HIF-1α-dependent manner. In vivo , HK Mtb induced TI when administered both systemically and intranasally, with the latter generating a more robust TI response. Summarizing, our research has demonstrated that HK Mtb has the potential to act as a mucosal immunotherapy that can successfully induce trained responses.