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

Autor: Camille R. Simoneau, Pei-Yi Chen, Galen K. Xing, Jennifer M. Hayashi, Irene P. Chen, Mir M. Khalid, Nathan L. Meyers, Taha Y. Taha, Kristoffer E. Leon, Rahul K. Suryawanshi, Maria McCavitt-Malvido, Tal Ashuach, Krystal A. Fontaine, Lauren Rodriguez, Bastian Joehnk, Keith Walcott, Sreelakshmi Vasudevan, Xiaohui Fang, Mazharul Maishan, Shawn Schultz, Jeroen P. Roose, Michael A. Matthay, Anita Sil, Mehrdad Arjomandi, Nir Yosef, Melanie Ott
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Scientific Reports, Vol 14, Iss 1, Pp 1-14 (2024)
Druh dokumentu: article
ISSN: 2045-2322
DOI: 10.1038/s41598-024-66003-2
Popis: 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.
Databáze: Directory of Open Access Journals
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