RT Journal Article SR Electronic T1 Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.07.17.452554 DO 10.1101/2021.07.17.452554 A1 Devin J. Kenney A1 Aoife K. O’Connell A1 Jacquelyn Turcinovic A1 Paige Montanaro A1 Ryan M. Hekman A1 Tomokazu Tamura A1 Andrew R. Berneshawi A1 Thomas R. Cafiero A1 Salam Al Abdullatif A1 Benjamin Blum A1 Stanley I. Goldstein A1 Brigitte L. Heller A1 Hans P. Gertje A1 Esther Bullitt A1 Alexander J. Trachtenberg A1 Elizabeth Chavez A1 Amira Sheikh A1 Susanna Kurnick A1 Kyle Grosz A1 Markus Bosmann A1 Maria Ericsson A1 Bertrand R. Huber A1 Mohsan Saeed A1 Alejandro B. Balazs A1 Kevin P. Francis A1 Alexander Klose A1 Neal Paragas A1 Joshua D. Campbell A1 John H. Connor A1 Andrew Emili A1 Nicholas A. Crossland A1 Alexander Ploss A1 Florian Douam YR 2021 UL http://biorxiv.org/content/early/2021/07/19/2021.07.17.452554.abstract AB 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.HIGHLIGHTSMice 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.Competing Interest StatementD.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.