Up-regulated pathways and GO Biological Processes in SARS-coV-2 infection suppressed by thalidomide and lenalidomide
SARS-coV-2 infected lungs, PBMC and A549 cells showed significant upregulation of expression of genes involved in inflammation, cytokine signaling, MAPK signaling and activation of cells mediating the immune response whereas BALF exhibited a slightly different immune profile where were leukocyte and neutrophil activation was suppressed (Figure 3A). Comparison of differentially expressed genes of all the signatures yielded interesting results. Many of the processes up-regulated in SARS-coV-2 infected tissues were suppressed by thalidomide and lenalidomide in A549 cells and endothelial cells (Figure 2A,2B,3A). Thalidomide-treated A549 cells showed suppression of key genes including SYK, JUN, PIK3CA and HLA genes implicated in immune response (Figure 3B, 3C). Thalidomide and lenalidomide down-regulated various pro-inflammatory and angiogenic genes aberrantly expressed in SARS-cov-2 infected lungs including CCL2 and TSC22D3 which are NF-κB modulators in A549 cells (Figure S3, S4). Thalidomide and lenalidomide treatment resulted in significantly suppression of cytokine response, angiogenesis, inflammation, Fc Epsilon receptor signaling and MAPK cascade (Figure 2A). In addition, lenalidomide down-regulated STAT1 expression, leukocyte differentiation, TLR signaling as well as IRF activation (Figure 2B, 4B). Many genes implicated in NOD-like receptor signaling overexpressed in SARS-coV-2 were suppressed by lenalidomide in A549 and lymphoma cells (Figure 4C). B cell receptor signaling was activated in SARS-coV-2 affected PBMC whereas T cell activation was observed in SARS-coV-2 lungs. Translation of viral mRNA was exclusively observed in SARS-coV-2 infected BALF whereas genes implicated in viral entry and life cycle were up-regulated in SARS-coV-2 infected lungs, BALF and A549 cells. Genes involved in viral entry and type I interferon signaling were down-regulated in thalidomide-treated A549 cells and lenalidomide-treated lymphoma, A549 and HUVEC (Figure 5A, 5C).