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. 20 human fetal lung xenografts implanted in mice. Four are uninfected, one is mock-infected with PBS, and 12 are infected with 1E+6 PFU of SARS-CoV-2. An additional 3 are uninfected xenografts contralateral to infected xenografts. 4 infected xenografts were harvested and sequenced at 2 DPI along with the 3 contralateral grafts. The remaining 8 infected xenografts were harvested at 7 DPI.