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 Sheikh; Susanna 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

doi:10.1016/j.celrep.2022.110714

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

Cell Rep. 2022 Apr 19;39(3):110714. doi: 10.1016/j.celrep.2022.110714. Epub 2022 Apr 4.

Authors

Devin J Kenney¹, Aoife K O'Connell¹, Jacquelyn Turcinovic², Paige Montanaro³, Ryan M Hekman⁴, Tomokazu Tamura⁵, Andrew R Berneshawi⁵, Thomas R Cafiero⁵, Salam Al Abdullatif⁶, Benjamin Blum⁴, Stanley I Goldstein⁴, Brigitte L Heller⁵, Hans P Gertje³, Esther Bullitt⁷, Alexander J Trachtenberg¹, Elizabeth Chavez¹, Evans Tuekam Nono¹, Catherine Morrison¹, Anna E Tseng¹, Amira Sheikh¹, Susanna Kurnick⁸, Kyle Grosz⁸, Markus Bosmann⁹, Maria Ericsson¹⁰, Bertrand R Huber¹¹, Mohsan Saeed¹², Alejandro B Balazs¹³, Kevin P Francis¹⁴, Alexander Klose¹⁵, Neal Paragas¹⁶, Joshua D Campbell⁶, John H Connor¹, Andrew Emili¹⁷, Nicholas A Crossland¹⁸, Alexander Ploss¹⁹, Florian Douam²⁰

Affiliations

¹ Department of Microbiology, Boston University School of Medicine, Boston, MA, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.
² National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA; Bioinformatics Program, Boston University, Boston, MA, USA.
³ National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
⁴ Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
⁵ Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
⁶ Single Cell RNA Sequencing Core, Boston University, Boston, MA, USA; Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁷ Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA.
⁸ National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA; Animal Science Center, Boston University, Boston, MA, USA.
⁹ Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany.
¹⁰ Electron Microscopy Core Facility, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹² National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
¹³ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
¹⁴ PerkinElmer, Hopkinton, MA, USA.
¹⁵ In Vivo Analytics, Inc., New York, NY, USA.
¹⁶ In Vivo Analytics, Inc., New York, NY, USA; Department of Radiology Imaging Research Lab, University of Washington, Seattle, WA, USA.
¹⁷ Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; Department of Biology, Boston University School of Medicine, Boston, MA, USA.
¹⁸ National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: [email protected].
¹⁹ Department of Molecular Biology, Princeton University, Princeton, NJ, USA. Electronic address: [email protected].
²⁰ Department of Microbiology, Boston University School of Medicine, Boston, MA, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA. Electronic address: [email protected].

Abstract

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
COVID-19* / genetics
Disease Models, Animal
Humans
Immunity, Innate
Lung / pathology
Macrophages
Mice
SARS-CoV-2

Abstract

Publication types

MeSH terms

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