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

Kenney, D. J.; O'Connell, A. K.; Turcinovic, J.; Montanaro, P.; Hekman, R. M.; Tamura, T.; Berneshawi, A. R.; Cafiero, T. R.; Al Abdullatif, S.; Blum, B.; Goldstein, S. I.; Heller, B.; Gertje, H. P.; Bullitt, E.; Trachtenberg, A. J.; Chavez, E.; Sheikh, A.; Kurnick, S.; Grosz, K.; Bosmann, M.; Ericsson, M.; Huber, B. R.; Saeed, M.; Balazs, A. B.; Francis, K. P.; Klose, A.; Paragas, N.; Campbell, J. D.; Connor, J. H.; Emili, A.; Crossland, N. A.; Ploss, A.; Douam, F.

doi:10.1101/2021.07.17.452554

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bioRxiv · 10.1101/2021.07.17.452554

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

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Abstract

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. HIGHLIGHTSO_LIMice engrafted with human fetal lung xenografts (fLX-mice) are highly susceptible to SARS-CoV-2. C_LIO_LICo-engraftment with a human myeloid-enriched immune system protected fLX-mice against infection. C_LIO_LITissue protection was defined by a potent and well-balanced antiviral response mediated by infiltrating macrophages. C_LIO_LIProtective IFN response was dominated by the upregulation of the USP18-ISG15 axis. C_LI

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Kenney, D. J., O'Connell, A. K., Turcinovic, J., Montanaro, P., Hekman, R. M., Tamura, T., Berneshawi, A. R., Cafiero, T. R., Al Abdullatif, S., Blum, B., Goldstein, S. I., Heller, B., Gertje, H. P., Bullitt, E., Trachtenberg, A. J., Chavez, E., Sheikh, A., Kurnick, S., Grosz, K., Bosmann, M., Ericsson, M., Huber, B. R., Saeed, M., Balazs, A. B., Francis, K. P., Klose, A., Paragas, N., Campbell, J. D., Connor, J. H., Emili, A., Crossland, N. A., Ploss, A., Douam, F.. 2021-07-19. Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection. https://doi.org/10.1101/2021.07.17.452554

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