LAUSR

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. Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled, by in vitro coculture, the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV-2–specific inflammatory gene cluster distinct from that seen in influenza A or Ebola virus-infected cocultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV-2 proteins (Spike and some nonstructural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV-2 induces in epithelia.