RT Journal Article
SR Electronic
T1 NF-κB inhibitor alpha has a cross-variant role during SARS-CoV-2 infection in ACE2-overexpressing human airway organoids
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.02.502100
DO 10.1101/2022.08.02.502100
A1 Camille R. Simoneau
A1 Pei-Yi Chen
A1 Galen K. Xing
A1 Mir M. Khalid
A1 Nathan L. Meyers
A1 Jennifer M. Hayashi
A1 Taha Y. Taha
A1 Kristoffer E. Leon
A1 Tal Ashuach
A1 Krystal A. Fontaine
A1 Lauren Rodriguez
A1 Bastian Joehnk
A1 Keith Walcott
A1 Sreelakshmi Vasudevan
A1 Xiaohui Fang
A1 Mazharul Maishan
A1 Shawn Schultz
A1 Jeroen Roose
A1 Michael A. Matthay
A1 Anita Sil
A1 Mehrdad Arjomandi
A1 Nir Yosef
A1 Melanie Ott
YR 2022
UL http://biorxiv.org/content/early/2022/08/02/2022.08.02.502100.abstract
AB As SARS-CoV-2 continues to spread worldwide, tractable primary airway cell models that accurately 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 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. NF-κB inhibitor alpha was consistently upregulated in infected epithelial cells, and its mRNA expression positively correlated with infection levels. Confocal microscopy showed more IκBα expression in infected than bystander cells, but found concurrent nuclear translocation of NF-κB that IκBα usually prevents. Overexpressing a nondegradable IκBα mutant reduced NF-κB translocation and increased viral infection. These data demonstrate the functionality of ACE2-OE organoids in SARS-CoV-2 research and identify an incomplete NF-κB feedback loop as a rheostat of viral infection that may promote inflammation and severe disease.Competing Interest StatementThe authors have declared no competing interest.