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 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 ### Competing Interest Statement D.K., A.K.O., J.T., P.M., R.M.H., T.T., A.R.B., T.R.C., S.A.A., B.B., S.I.G., B.L.H., H.P.G., E.B., A.T., E.C., A.S., S.K., K.G., M.B., M.A., B.R.H., M.S., A.B.B., J.D.C. J.H.C., A.E., N.A.C., A.P. and F.D declare no conflict of interest. K.P.F. reports that he is an employee of PerkinElmer, Inc., manufacturer of diagnostic and analytical equipment. N.P. and A.K. declare the following competing interest as shareholders of InVivo Analytics with issued patents.