Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Chromatin accessibility as assessed by histone modifications at the level of promotors (H3K4me3, H3K27Ac) or enhancers (H3K4me1) is an important mechanism mediating these programs. Through network-level integration of transcriptomics, epigenetics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by beta-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming. Furthermore, fumarate itself induces trained immunity, with induction of an epigenomic program similar to β-glucan-induced trained immunity. Identification of the molecular pathways contributing to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues. Finally, the use of live attenuated vaccines such as BCG can induce beneficial heterologous effects in infections and cancer.
About Mihai Netea
Mihai Netea was born and studied medicine in Cluj-Napoca, Romania. He completed his PhD at the Radboud University Nijmegen, The Netherlands, on studies investigating the cytokine network in sepsis. After working as a post-doc at the University of Colorado, he returned to Nijmegen where he finished his clinical training as an infectious diseases specialist, and where he currently heads the division of Experimental Medicine, Department of Internal Medicine, Nijmegen University Nijmegen Medical Center. He is mainly interested in understanding the factors influencing variability of human immune responses, the biology of sepsis and immunoparalysis in bacterial and fungal infections, and the study of the memory traits of innate immunity. He is the recipient of the Spinoza Prize 2016 and an ERC Advanced grant in 2019, and member of the Netherlands Royal Academy of Science (KNAW).
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