Radboud University Nijmegen - Department of Internal Medicine; Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI); Statens Serums Institut - Research Center for Vitamins and Vaccines; University of Southern Denmark - Odense Patient Data Explorative Network (OPEN)
Radboud University Nijmegen - Department of Internal Medicine; Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI); Statens Serums Institut - Research Center for Vitamins and Vaccines; University of Southern Denmark - Odense Patient Data Explorative Network (OPEN)
Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the underlying mechanisms regulating the longevity and magnitude of such effects remain elusive. We show that BCG vaccination in humans induces the long-lasting activation of a transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell compartment in the bone marrow. As crucial regulators of this transcriptional shift we identify hepatic nuclear factor family members 1a and b. These findings are corroborated by higher granulocyte numbers in BCG- vaccinated infants, HNF1 SNP variants correlating with trained immunity, and elevated serum concentrations of the HNF1 target gene SERPINA1. In addition, transcriptomic HSPC remodelling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature 3 months after BCG vaccination. Taken together, transcriptomic, epigenomic and functional reprogramming of HSPCs and peripheral monocytes is pivotal in human in vivo BCG-induced trained immunity.
Cirovic, B. and de Bree, L. C. J. and Groh, L. and Blok, B. A. and Chan, J. and Velden, W.J.F.M. van der and Bremmers, M. E. J. and van Crevel, Reinout and Händler, K. and Picelli, S. and Schulte-Schrepping, J. and Klee, K. and Oosting, M. and Li, Y. and Benn, C. S. and Schultze, Joachim L. and Joosten, L. A. B. and Curtis, N. and Netea, M. G. and Schlitzer, Andreas, Human Bacille Calmette-Guérin Vaccination Elicits Trained Immunity Via the Hematopoietic Progenitor Compartment. Available at SSRN: https://ssrn.com/abstract=3376658 or http://dx.doi.org/10.2139/ssrn.3376658
This version of the paper has not been formally peer reviewed.
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