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Background: Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated., Objective: We combined functional immunological assays and an omics-based approach to investigate the in vitro and in vivo effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients., Methods: Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed., Results: Dexamethasone efficiently inhibited SARS-CoV-2-induced in vitro expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated ex vivo with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses., Conclusion: We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Engel, van der Made, Keur, Setiabudiawan, Röring, Damoraki, Dijkstra, Lemmers, Ioannou, Poulakou, van der Meer, Giamarellos-Bourboulis, Kumar, van de Veerdonk, Netea and Ziogas.)

Trained immunity is a long-term increase in responsiveness of innate immune cells, induced by certain infections and vaccines. During the last 3 years of the COVID-19 pandemic, vaccines that induce trained immunity, such as BCG, MMR, OPV, and others, have been investigated for their capacity to protect against COVID-19. Further, trained immunity-inducing vaccines have been shown to improve B and T cell responsiveness to both mRNA- and adenovirus-based anti-COVID-19 vaccines. Moreover, SARS-CoV-2 infection itself induces inappropriately strong programs of trained immunity in some individuals, which may contribute to the long-term inflammatory sequelae. In this review, we detail these and other aspects of the role of trained immunity in SARS-CoV-2 infection and COVID-19. We also examine the learnings from the trained immunity studies conducted in the context of this pandemic and discuss how they may help us in preparing for future infectious outbreaks., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The innate immune system is able to build memory-like features in response to certain infections or vaccines, resulting in enhanced responsiveness upon (re)challenge with the same or an unrelated pathogen, a phenomenon termed 'trained immunity'. Compared with antigen-dependent adaptive immune responses triggered by classical vaccines against specific pathogens, trained immunity-related vaccines induce enhanced innate immune responses against unrelated pathogens and provide 'heterologous protection'. Here, we discuss the heterologous effects of vaccines against infections and detail the latest insights into the cellular and molecular mechanisms mediating trained immunity. Additionally, novel vaccine strategies are suggested for fighting new pandemics in the future by taking advantage of the heterologous memory features of trained immunity. Trained innate immune cells have improved antimicrobial function mediated by transcriptional and epigenetic rewiring. Long-lasting trained immunity is centrally regulated in hematopoietic progenitors in the bone marrow and peripherally induced in tissue-resident cells. Distinct trained immunity programs at the single cell level identify trained monocyte subpopulations. Heterologous or nonspecific protection of vaccines against unrelated pathogens can be partially explained by induction of trained immunity responses. BCG, MTBVAC, influenza, measles, and possibly the new mRNA Coronavirus 2019 (COVID-19) vaccines induce trained immunity signatures, while trained immunity inducers can act as vaccine adjuvants. Environmental factors, the microbiome, circadian rhythm, genetics, and sex influence vaccine-induced trained immunity heterogeneity. [ABSTRACT FROM AUTHOR]