Significance By modeling in vitro the cross-talk between epithelial and immune cells, this work provides possible origins for the profound inflammatory perturbations that are a hallmark of COVID-19, and the relative protection of children from severe disease. The initial interaction between immune cells and epithelial cells infected with SARS-CoV-2, or transduced to express the proteins the virus encodes, elicits a specific response, not observed with other pathogenic viruses, that presages perturbations seen in patients with severe COVID-19. Thus, the severe manifestations of COVID-19 may be rooted in the very first response that it elicits from immunocytes.