Severe COVID-19 shares a common neutrophil activation signature with other acute inflammatory states

Abstract

Clinical and hyperinflammatory overlap between COVID-19 and hemophagocytic lymphohistiocytosis (HLH) has been reported. However, the underlying mechanisms are unclear. Here we show that COVID-19 and HLH have an overlap of signaling pathways and gene signatures commonly dysregulated, which were defined by investigating the transcriptomes of 1253 subjects (controls, COVID-19, and HLH patients) using microarray, bulk RNA-sequencing (RNAseq), and single-cell RNAseq (scRNAseq). COVID-19 and HLH share pathways involved in cytokine and chemokine signaling as well as neutrophil-mediated immune responses that associate with COVID-19 severity. These genes are dysregulated at protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins which converge to neutrophil hyperactivation in COVID-19 patients admitted to intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.

The relationship between autoantibodies targeting GPCRs and the renin-angiotensin system associates with COVID-19 severity

“…CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) expressed by effector T cells controlling the traffic and function of CD4+ and CD8+ T cells during inflammation [60][61][62][63] . Further, CXCR3 has been strongly associated with both autoimmune and inflammatory diseases 64 .…”

“…There is an essential biological connection between CXCR3 and AT1R. Blocking AT1R impairs the release of several chemokines, including CXCL10, the ligand for CXCR3 59 , a chemokine receptor highly expressed by effector T cells controlling the traffic and function of CD4+ and CD8+ T cells during inflammation [60][61][62][63] . Further, CXCR3 has been strongly associated with both autoimmune and inflammatory diseases 64 .…”

Integrative systems vaccinology identification of shared gene signatures between natural dengue infection and vaccination trials

“…We obtained differentially expressed genes (DEGs) for the microarray studies (GSE28405, GSE28988, GSE28991, GSE43777, GSE98053, and GSE94892) and RNAseq data sets (GSE51808, GSE152255, and GSE146658) using the limma-voom pipeline 66 as recently described [67][68][69] . We applied the statistical cut-offs of adjusted p-value < 0.05, log2 fold-change (logFC) > 1 (up-regulated) or < -1 (down-regulated) to determine the DEGs.…”

“…We used random forest 76 to rank DEGs as predictors of dengue phases using the R package random Forest (version 4.6.14) as previously described 69,77 . Briefly, five thousand trees were used, and the number of variables resampled were equal to three.…”

“…Principal Component Analysis (PCA) of NDI-DVTs genes (log2 transformed values) that were DEGs in GSE43777 was performed using the R functions prcomp and princomp, through factoextra 78 and FactoMineR package 79 . We also visualized DEGs belonging to NDI-DVTs gene sets in GSEs 43777, 51808, 94892, and 152255 through boxplots using the ggpubr, lemon, and ggplot2 packages using the statistical Wilcoxon sum-rank test as previously described 69 .…”