Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection

Kenney, Devin J.; O’Connell, Aoife K.; Turcinovic, Jacquelyn; Montanaro, Paige; Hekman, Ryan M.; Tamura, Tomokazu; Berneshawi, Andrew R.; Cafiero, Thomas R.; Abdullatif, Salam Al; Blum, Benjamin; Goldstein, Stanley I.; Heller, Brigitte L.; Gertje, Hans P.; Bullitt, Esther; Trachtenberg, Alexander J.; Chavez, Elizabeth; Sheikh, Amira; Kurnick, Susanna; Grosz, Kyle; Bosmann, Markus; Ericsson, Maria; Huber, Bertrand R.; Saeed, Mohsan; Balazs, Alejandro B.; Francis, Kevin P.; Klose, Alexander; Paragas, Neal; Campbell, Joshua D.; Connor, John H.; Emili, Andrew; Crossland, Nicholas A.; Ploss, Alexander; Douam, Florian

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 protected against 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 pronounced 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 light on unique cellular and molecular correlates of lung tissue protection during SARS-CoV-2 infection, and underscores macrophage IFN responses as prime targets for developing immunotherapies against coronavirus respiratory diseases. HIGHLIGHTS Mice engrafted with human fetal lung xenografts (fLX-mice) are highly susceptible to SARS-CoV-2. Co-engraftment with a human myeloid-enriched immune system protected fLX-mice against infection. Tissue protection was defined by a potent and well-balanced antiviral response mediated by infiltrating macrophages. Protective IFN response was dominated by the upregulation of the USP18-ISG15 axis.