Two major biological signatures associated with the progression from mild to moderate and severe disease emerged from our integrated analysis: (1) the dampening of NF-κB, MAPK/mTOR, and JAK/STAT intracellular signaling responses in multiple innate and adaptive immune cell subsets, and (2) the mobilization of a proteomic network enriched for elements of the RAS, lung homeostasis, and hemostasis pathways, alongside canonical elements of the cytokine storm signature of severe COVID-19. This evidence concerns the gene SOAT1 and COVID-19.