Genome-wide and single-cell RNA-seq analyses further confirmed the activation of the TLR4/MAPK14/RELA/IL-1β axis in circulating ECs in patients with mild and severe COVID-19, indicating that human ECs were not protected from SARS-CoV-2-mediated activation by being ACE2-deficient as they still recognized and responded to the virus through TLR4 activation. This evidence concerns the gene TLR4 and COVID-19.