An integrative genomics approach identifies KDM4 as a modulator of trained immunity.

Simone J C F M Moorlag, Vasiliki Matzaraki, Jelmer H van Puffelen, Charlotte van der Heijden, Sam Keating, Laszlo Groh, Rutger Jan Röring, Olivier B Bakker, Vera P Mourits, Valerie A C M Koeken, L Charlotte J de Bree, Sanne P Smeekens, Marije Oosting, Raúl Aguirre Gamboa, Niels P Riksen, Ramnik J Xavier, Cisca Wijmenga, Vinod Kumar, Reinout van Crevel, Boris Novakovic, Leo A B Joosten, Yang Li, Mihai G Netea

Journal: European journal of immunology 2022;52(3):431-446

PMID: 34821391

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Abstract

Innate immune cells are able to build memory characteristics via a process termed "trained immunity." Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.

Address: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Genetics, University Medical Center Groningen, University of Groningenor, Groningen, The Netherlands.; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.; Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Odense, Denmark.; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Genetics, University Medical Center Groningen, University of Groningenor, Groningen, The Netherlands.; K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Norway.; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Genetics, University Medical Center Groningen, University of Groningenor, Groningen, The Netherlands.; Epigenetics, Murdoch Children's Research Institute, Royal Children's Hospital, and Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, Helmholtz Centre for Infection Research, Hannover Medical School, Hannover, Germany.; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.

DOI: 10.1002/eji.202149577

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MeSH Terms: BCG Vaccine, Genomics, Humans, Immunity, Innate, Phosphatidylinositol 3-Kinases, Sialic Acid Binding Immunoglobulin-like Lectins