Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection
SUMMARY 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.HIGHLIGHTS <jats:list list-type="bullet">Mice 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..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 04. Jan. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2021.07.17.452554 |
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| PPN (Katalog-ID): |
XBI03833173X |
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| 100 | 1 | |a Kenney, Devin J. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection |
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| 520 | |a SUMMARY 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.HIGHLIGHTS <jats:list list-type="bullet">Mice 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. | ||
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| 700 | 1 | |a Montanaro, Paige |e verfasserin |4 aut | |
| 700 | 1 | |a Hekman, Ryan M. |e verfasserin |4 aut | |
| 700 | 1 | |a Tamura, Tomokazu |e verfasserin |4 aut | |
| 700 | 1 | |a Berneshawi, Andrew R. |e verfasserin |4 aut | |
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| 700 | 1 | |a Abdullatif, Salam Al |e verfasserin |4 aut | |
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