Single-cell RNA sequencing reveals induction of distinct trained-immunity programs in human monocytes
Bowen Zhang, Simone J.C.F.M Moorlag, Jorge Dominguez-Andres, Özlem Bulut, Gizem Kilic, Zhaoli Liu, Reinout van Crevel, Cheng-Jian Xu, Leo A.B. Joosten, Mihai G. Netea, Yang Li
Bowen Zhang, Simone J.C.F.M Moorlag, Jorge Dominguez-Andres, Özlem Bulut, Gizem Kilic, Zhaoli Liu, Reinout van Crevel, Cheng-Jian Xu, Leo A.B. Joosten, Mihai G. Netea, Yang Li
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Research Article Immunology Infectious disease

Single-cell RNA sequencing reveals induction of distinct trained-immunity programs in human monocytes

Abstract

Trained immunity refers to the long-lasting memory traits of innate immunity. Recent studies have shown that trained immunity is orchestrated by sustained changes in epigenetic marks and metabolic pathways, leading to an altered transcriptional response to a second challenge. However, the potential heterogeneity of trained-immunity induction in innate immune cells has not been explored. In this study, we demonstrate cellular transcriptional programs in response to 4 different inducers of trained immunity in monocyte populations at single-cell resolution. Specifically, we identified 3 monocyte subpopulations upon the induction of trained immunity, and replicated these findings in an in vivo study. In addition, we found gene signatures consistent with these functional programs in patients with ulcerative colitis, sepsis, and COVID-19, suggesting the impact of trained-immunity programs in immune-mediated diseases.

Authors

Bowen Zhang, Simone J.C.F.M Moorlag, Jorge Dominguez-Andres, Özlem Bulut, Gizem Kilic, Zhaoli Liu, Reinout van Crevel, Cheng-Jian Xu, Leo A.B. Joosten, Mihai G. Netea, Yang Li

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Figure 7

In vivo validation of trained-immunity signatures.

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In vivo validation of trained-immunity signatures. (A) Study design. Hea...
(A) Study design. Healthy human volunteers (n = 3) were vaccinated with BCG. Before vaccination and 90 days later, PBMCs were isolated and restimulated ex vivo with RPMI culture medium (control) or LPS. (B) UMAP of PBMCs showing cells before and after BCG vaccination, with or without LPS restimulation from the in vivo study. (C) UMAP of AUC scores in monocytes after BCG vaccination. (D) UMAP of cell trajectory of monocytes after BCG vaccination, annotated by assigned trained subgroups. (E) Heatmap showing log(fold change) of 6 marker genes (rows) in monocytes 90 days after BCG vaccination (column) relative to the average expression before vaccination. Red and blue colors correspond to upregulation and downregulation, respectively. (F) Dot heatmap of expression of shared training response (TR) genes detected in LPS-restimulated cells from trained subgroups in both in vivo and in vitro training experiments. Gene expression is shown as log(fold change) relative to the average of RPMI control groups in the in vitro study, and relative to time point before vaccination for the in vivo study. (G) KEGG enrichment of TR genes of the in vivo study in each subgroup of trained cells.