Heat-killed Mycobacterium tuberculosis induces trained immunity in vitro and in vivo administered systemically or intranasally
Luna Minute,
Marta Bergón-Gutiérrez,
Pablo Mata-Martínez,
Jaime Fernández-Pascual,
Verónica Terrón,
Laura Bravo-Robles,
Gülce Bıçakcıoğlu,
Gabriela Zapata-Fernández,
Nacho Aguiló,
Eduardo López-Collazo,
Carlos del Fresno
Affiliations
Luna Minute
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
Marta Bergón-Gutiérrez
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
Pablo Mata-Martínez
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
Jaime Fernández-Pascual
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
Verónica Terrón
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Tumor Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
Laura Bravo-Robles
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
Gülce Bıçakcıoğlu
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
Gabriela Zapata-Fernández
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
Nacho Aguiló
Department of Microbiology, Pediatrics, Radiology, and Public Health, University of Zaragoza/IIS Aragon, Zaragoza, Spain; CIBERES, CIBERINFEC, Carlos III Health Institute, Madrid, Spain
Eduardo López-Collazo
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Tumor Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain; CIBERES, CIBERINFEC, Carlos III Health Institute, Madrid, Spain
Carlos del Fresno
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain; Corresponding author
Summary: 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 (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.
