Here, we found that infection with SARS-CoV-2 induced a strong interferon response in ALI and iALI cultures, marked by a high expression of ISG15 (key factor in the innate immune response to SARS-CoV-2 infection), ISG20 (with antiviral activity against RNA viruses), IRF-7 (the master regulator of interferon responses) [47] and of several ISGs (IFITM1, IFITM3, IRF9, IFI27, OAS2, MX1, MX2, SOCS3) involved in the regulation of the host defense responses to the virus [48]. This evidence concerns the gene ISG15 and infection.