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

doi:10.1016/j.isci.2024.108869

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

iScience. 2024 Jan 11;27(2):108869. doi: 10.1016/j.isci.2024.108869. eCollection 2024 Feb 16.

Authors

Luna Minute^{1

2}, Marta Bergón-Gutiérrez^{1

2}, Pablo Mata-Martínez^{1

2}, Jaime Fernández-Pascual^{1

2}, Verónica Terrón^{1

3}, Laura Bravo-Robles^{1

2}, Gülce Bıçakcıoğlu^{1

2}, Gabriela Zapata-Fernández^{1

2}, Nacho Aguiló^{4

5}, Eduardo López-Collazo^{1

3

5}, Carlos Del Fresno^{1

2}

Affiliations

¹ The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.
² Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain.
³ Tumor Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain.
⁴ Department of Microbiology, Pediatrics, Radiology, and Public Health, University of Zaragoza/IIS Aragon, Zaragoza, Spain.
⁵ CIBERES, CIBERINFEC, Carlos III Health Institute, Madrid, Spain.

Abstract

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.

Keywords: Immune response; Microbiology; Therapy.