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. 2020 Nov 10;184(2):460–475.e21. doi: 10.1016/j.cell.2020.11.007

Figure 3.

Figure 3

Baricitinib treatment suppresses gene expression of inflammation and neutrophil degranulation in the BALs of SARS-CoV-2-infected RMs

Bulk RNA-seq profiles of BAL cell suspensions from RMs obtained at day −5 prior to SARS-CoV-2 inoculation (baseline), at 2 days after infection, prior to baricitinib treatment, and at 4 days after infection, 2 days after initiation of baricitinib.

(A) Venn diagrams indicating the number of differential expression genes (DEGs) detected at 2 or 4 days after infection relative to −5 days after infection in the untreated (red) and baricitinib-treated (blue) groups. The total DEGs for each comparison are shown in parentheses.

(B) Bar plots showing enrichment of top scoring inflammatory and immunological gene signatures from the MSIGDB (Hallmark and Canonical Pathways) and databases, and custom gene sets (interferon-stimulated genes [ISGs]; see below) ranked by GSEA comparisons of gene expression in the 4 days after infection versus 2 days after infection samples from the untreated (red bars) and baricitinib-treated (blue bars) groups. The x axis depicts the normalized enrichment score (NES); a positive enrichment score indicated higher expression at 4 days after infection relative to 2 days after infection (bars facing right); conversely, negative scores of a pathway indicate cumulatively higher expression in 2 days after infection samples relative to 4 days after infection (bars facing left). Nominal p values are indicated.

(C–F) GSEA enrichment plots depicting pairwise comparison of gene expression of 2 days after infection versus 4 days after infection samples for the untreated group and for the baricitinib-treated group. The top-scoring (i.e., leading edge) genes are indicated by solid dots. The hash plot under GSEA curves indicates individual genes and their rank in the dataset. Left-leaning curves (i.e., positive enrichment scores) indicate higher expression of pathways at 4 days after infection; right-leaning curves (negative enrichment scores) indicate higher expression at 2 days after infection. Sigmoidal curves indicate equivalent expression between the groups being compared. The NES and nominal p values testing the significance of each comparison are indicated. (C) REACTOME_ NEUTROPHIL_DEGRANULATION (MSIDB #M27620). (D) GSEA line plot of HALLMARK_TNFA_SIGNALING_VIA_NFKB pathway (MSIGDB #M5890). (E) GSEA line plot of HALLMARK_IL6_JAK_STAT3_SIGNALING (MSIGDB #M5897). (F) A custom gene set of ISGs from prior NHP studies (Nganou-Makamdop et al., 2018; Palesch et al., 2018; Sandler et al., 2014).

(G–J) Heatmaps of top-scoring (i.e., leading edge) from the untreated 4 days after infection versus 2 days after infection GSEA analyses. The color scale indicates the log2 expression relative to the median of all baseline samples.

See also Figure S3.