NF-κB inhibitor alpha controls SARS-CoV-2 infection in ACE2-overexpressing human airway organoids.

Autor: Simoneau CR; Gladstone Institute of Virology, San Francisco, CA, USA.; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA., Chen PY; Gladstone Institute of Virology, San Francisco, CA, USA., Xing GK; Chan-Zuckerberg Biohub, San Francisco, CA, USA.; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA., Hayashi JM; Gladstone Institute of Virology, San Francisco, CA, USA., Chen IP; Gladstone Institute of Virology, San Francisco, CA, USA.; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA., Khalid MM; Gladstone Institute of Virology, San Francisco, CA, USA., Meyers NL; Gladstone Institute of Virology, San Francisco, CA, USA., Taha TY; Gladstone Institute of Virology, San Francisco, CA, USA., Leon KE; Gladstone Institute of Virology, San Francisco, CA, USA.; Medical Scientist Training Program, University of California San Francisco, San Francisco, CA, USA., Suryawanshi RK; Gladstone Institute of Virology, San Francisco, CA, USA., McCavitt-Malvido M; Gladstone Institute of Virology, San Francisco, CA, USA., Ashuach T; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA., Fontaine KA; Gladstone Institute of Virology, San Francisco, CA, USA., Rodriguez L; ImmunoX CoLabs, University of California San Francisco, San Francisco, CA, USA., Joehnk B; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA., Walcott K; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA., Vasudevan S; Medical Service, San Francisco VA Healthcare System, San Francisco, CA, USA., Fang X; Department of Medicine and Department of Anesthesia, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA., Maishan M; Department of Medicine and Department of Anesthesia, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA., Schultz S; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA., Roose JP; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA., Matthay MA; Department of Medicine and Department of Anesthesia, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA., Sil A; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA., Arjomandi M; Medical Service, San Francisco VA Healthcare System, San Francisco, CA, USA.; Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Yosef N; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA. nir.yosef@weizmann.ac.il.; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. nir.yosef@weizmann.ac.il., Ott M; Gladstone Institute of Virology, San Francisco, CA, USA. melanie.ott@gladstone.ucsf.edu.; Chan-Zuckerberg Biohub, San Francisco, CA, USA. melanie.ott@gladstone.ucsf.edu.; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. melanie.ott@gladstone.ucsf.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jul 04; Vol. 14 (1), pp. 15351. Date of Electronic Publication: 2024 Jul 04.
DOI: 10.1038/s41598-024-66003-2
Abstrakt: As SARS-CoV-2 continues to spread worldwide, tractable primary airway cell models that recapitulate the cell-intrinsic response to arising viral variants are needed. Here we describe an adult stem cell-derived human airway organoid model overexpressing the ACE2 receptor (ACE2-OE) that supports robust viral replication while maintaining 3D architecture and cellular diversity of the airway epithelium. ACE2-OE organoids were infected with SARS-CoV-2 variants and subjected to single-cell RNA-sequencing. Interferon-lambda was upregulated in cells with low-level infection while the NF-kB inhibitor alpha gene (encoding IkBa) was consistently upregulated in infected cells, and its expression positively correlated with infection levels. Confocal microscopy showed more IkBa expression in infected than bystander cells, but found concurrent nuclear translocation of NF-kB that IkBa usually prevents. Overexpressing a nondegradable IkBa mutant reduced NF-kB translocation and increased viral infection. These data demonstrate the functionality of ACE2-OE organoids in SARS-CoV-2 research and underscore that the strength of the NF-kB feedback loop in infected cells controls viral replication.
(© 2024. The Author(s).)
Databáze: MEDLINE
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