doi:10.1016/j.isci.2024.108869engMinute, LunaBergón-Gutiérrez, MartaMata-Martínez, PabloFernández-Pascual, JaimeTerrón, VerónicaBravo-Robles, LauraBiçakcioglu, GülceZapata-Fernández, GabrielaAguiló, NachoLópez-Collazo, Eduardodel Fresno, CarlosHeat-killed Mycobacterium tuberculosis induces trained immunity in vitro and in vivo administered systemically or intranasallyART-2024-137697Trained 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 (HKMtb) induces TI both in vitro and in vivo. In human monocytes, this effect represents a truly trained process, as HKMtb confers boosted inflammatory responses against various heterologous challenges, such as lipopolysaccharide (Toll-like receptor [TLR] 4 ligand) and R848 (TLR7/8 ligand). Mechanistically, HKMtb-induced TI relies on epigenetic mechanisms in a Syk/HIF-1α-dependent manner. In vivo, HKMtb induced TI when administered both systemically and intranasally, with the latter generating a more robust TI response. Summarizing, our research has demonstrated that HKMtb has the potential to act as a mucosal immunotherapy that can successfully induce trained responses.2024http://zaguan.unizar.es/record/13277910.1016/j.isci.2024.108869http://zaguan.unizar.es/record/132779oai:zaguan.unizar.es:132779ISCIENCE 27, 2 (2024), 108869 [16 pp.]by-nc-ndhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.esinfo:eu-repo/semantics/openAccess