Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection

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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


The human immunological mechanisms defining the clinical outcome of SARS-CoV-2 infection remain elusive. This knowledge gap is mostly driven by the lack of appropriate experimental platforms recapitulating human immune responses in a controlled human lung environment. Here, we report a mouse model (i.e., HNFL mice) co-engrafted with human fetal lung xenografts (fLX) and a myeloid-enhanced human immune system to identify cellular and molecular correlates of lung protection during SARS-CoV-2 infection. Unlike mice solely engrafted with human fLX, HNFL mice are protected against infection, severe inflammation, and histopathological phenotypes. Lung tissue protection from infection and severe histopathology associates with macrophage infiltration and differentiation and the upregulation of a macrophage-enriched signature composed of 11 specific genes mainly associated with the type I interferon signaling pathway. Our work highlights the HNFL model as a transformative platform to investigate, in controlled experimental settings, human myeloid immune mechanisms governing lung tissue protection during SARS-CoV-2 infection.

Original languageEnglish (US)
Article number110714
JournalCell Reports
Issue number3
StatePublished - Apr 19 2022
Externally publishedYes


  • antiviral responses
  • COVID-19
  • CP: Immunology
  • CP: Microbiology
  • human immune responses to SARS-CoV-2
  • humanized mice
  • macrophage responses to SARS-CoV-2
  • mouse models of SARS-CoV-2
  • pulmonary immune responses

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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