BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

• Published in: Cell Host & Microbe 2018-01, Vol.23 (1), p.89-100.e5
• Main Authors: Arts, Rob J.W., Moorlag, Simone J.C.F.M., Novakovic, Boris, Li, Yang, Wang, Shuang-Yin, Oosting, Marije, Kumar, Vinod, Xavier, Ramnik J., Wijmenga, Cisca, Joosten, Leo A.B., Reusken, Chantal B.E.M., Benn, Christine S., Aaby, Peter, Koopmans, Marion P., Stunnenberg, Hendrik G., van Crevel, Reinout, Netea, Mihai G.
• Format: Article
• Language: English
• Subjects: Adult; BCG; BCG Vaccine - immunology; Cellular Reprogramming - genetics; Epigenesis, Genetic - genetics; epigenetics; Humans; IL-1; innate immune memory; Interferon-gamma - blood; Interleukin-1beta - blood; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Male; monocytes; Monocytes - immunology; Mycobacterium bovis - immunology; non-specific effects of vaccines; Polymorphism, Single Nucleotide - genetics; trained immunity; Vaccination; Viremia - prevention & control; Virus Diseases - immunology; Virus Diseases - prevention & control; Yellow Fever - immunology; Yellow Fever - prevention & control; Yellow Fever - virology; yellow fever vaccine; Yellow fever virus - immunology; Young Adult
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2017.12.010

The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses. [Display omitted] •BCG vaccination of humans induces genome-wide epigenetic reprogramming in monocytes•BCG-induced changes correlate with protection against experimental virus infection•Viremia reduction correlates with IL-1β upregulation, indicative of trained immunity•SNPs in IL1B affect the induction of trained immunity by BCG In this paper, Arts et al. describe that BCG vaccination induces genome-wide epigenetic reprogramming of human monocytes that correlates with protection against experimental viral infection. Reduction of viremia correlated with upregulation of non-specific IL-1β production, and genetic polymorphisms in the IL-1 pathway affect the induction of trained immunity by BCG.