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).