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

Authors :
Simoneau, Camille R.
Chen, Pei-Yi
Xing, Galen K.
Hayashi, Jennifer M.
Chen, Irene P.
Khalid, Mir M.
Meyers, Nathan L.
Taha, Taha Y.
Leon, Kristoffer E.
Suryawanshi, Rahul K.
McCavitt-Malvido, Maria
Ashuach, Tal
Fontaine, Krystal A.
Rodriguez, Lauren
Joehnk, Bastian
Walcott, Keith
Vasudevan, Sreelakshmi
Fang, Xiaohui
Maishan, Mazharul
Schultz, Shawn
Source :
Scientific Reports; 7/4/2024, Vol. 14 Issue 1, p1-14, 14p
Publication Year :
2024

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20452322
Volume :
14
Issue :
1
Database :
Complementary Index
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
178276480
Full Text :
https://doi.org/10.1038/s41598-024-66003-2