SRP328272 PRJNA746455 GSE180063 Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection The majority of SARS-CoV-2 infections among healthy individuals result in asymptomatic to mild disease. However, the immunological mechanisms defining effective lung tissue protection from SARS-CoV-2 infection remain elusive. Unlike mice solely engrafted with human fetal lung xenograft (fLX), mice co-engrafted with fLX and a myeloid-enhanced human immune system (HNFL mice) are resistant to SARS-CoV-2 infection, severe inflammation, and histopathology. Effective control of viral infection in HNFL mice associated with significant macrophage infiltration, and the induction of a potent macrophage-mediated interferon response. The strong upregulation of the USP18-ISG15 axis, a negative regulator of IFN responses, by macrophages was unique to HNFL mice and represented a prominent correlate of reduced inflammation and histopathology. Altogether, our work shed lights on unique cellular and molecular correlate of lung tissue protection during SARS-CoV-2 infection, and underscores macrophage IFN responses as prime targets for developing immunotherapies against coronavirus respiratory diseases. Overall design: 12 human fetal lung xenografts implanted in mice: 4- Naïve (non-inoculated in non-infected mice) human fetal lung xenografts from NRG-L mice. 3-human fetal lung xenografts from NRG-Flk2-/- mice co-engrafted with a human immune system at 2-days and 7-days post infection using 1x10^6 PFU SARS-CoV-2 WA-Isolate. 3 Naïve (non-infected graft in non-infected mice) human fetal lung xenografts from NRG-Flk2-/- mice co-engrafted with a human system were sequenced as a control. GSE180063 pubmed 35421379