The human immunological mechanisms defining the clinical outcome of viral respiratory infections remain elusive. This knowledge gap is mostly driven by the lack of appropriate experimental platforms recapitulating human myeloid immune responses in a human lung environment. Here, we report a novel mouse model (i.e. HNFL mice) co-engrafted with human fetal lung xenografts (fLX) and a myeloid-enhanced human immune system. Using a combination of multi-omics approach and SARS-CoV-2 as prototypical respiratory virus, we demonstrate that HNFL represent a promising platform to identify cellular and molecular correlates of lung tissue protection during viral respiratory infection. Unlike mice solely engrafted with human fLXs, HNFL mice are protected against SARS-CoV-2 infection, severe inflammation, and histopathological phenotypes. We found that lung tissue protection from SARS-CoV-2 infection and severe histopathology associated with macrophage infiltration, and the induction of a potent macrophage-mediated antiviral response dominated by the upregulation of the USP18-ISG15 axis. Our work highlights the HNFL model as a transformative platform for the immunology community to investigate in controlled experimental settings human myeloid immune mechanisms governing lung tissue protection.
