Abstract | BACKGROUND: METHODS: Therefore, in this work we assessed the effect of exposure (24 h) to 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n = 6 per exposure condition). Corresponding sham exposed samples served as a control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes (NCI-H441). RESULTS: Exposure to S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p ≤ 0.01). Pathway analysis revealed enrichment of canonical pathways such as interferon (IFN) signaling, influenza, coronavirus, and anti-viral response in the bro-ALI. Secreted levels of interleukin (IL) 4 and IL12 were significantly (p < 0.05) increased, whereas IL6 decreased in the bro-ALI. In the case of alv-ALI, enriched terms involving p53, APRIL (a proliferation-inducing ligand) tight junction, integrin kinase, and IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p < 0.05) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL13, and tumor necrosis factor alpha were detected in alv-ALI, whereas IL12 was decreased. Altered levels of these cytokines are also associated with lung fibrotic response. CONCLUSIONS: In conclusion, we observed a typical anti-viral response in the bronchial model and a pro-fibrotic response in the alveolar model. The bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of SARS-CoV-2 variants of concern at different lung regions.
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Authors | Mizanur Rahman, Martin Irmler, Sandeep Keshavan, Micol Introna, Johannes Beckers, Lena Palmberg, Gunnar Johanson, Koustav Ganguly, Swapna Upadhyay |
Journal | Viruses
(Viruses)
Vol. 13
Issue 12
(12 17 2021)
ISSN: 1999-4915 [Electronic] Switzerland |
PMID | 34960806
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cytokines
- Recombinant Proteins
- Spike Glycoprotein, Coronavirus
- TLR2 protein, human
- TLR4 protein, human
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- spike protein, SARS-CoV-2
- ACE2 protein, human
- Angiotensin-Converting Enzyme 2
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Topics |
- Angiotensin-Converting Enzyme 2
(metabolism)
- Bronchi
(metabolism)
- Cytokines
(metabolism)
- Gene Expression Profiling
- Humans
- Lung
(metabolism)
- Models, Biological
- Protein Interaction Domains and Motifs
- Recombinant Proteins
(chemistry, metabolism)
- Respiratory Mucosa
(metabolism)
- SARS-CoV-2
(metabolism, pathogenicity)
- Spike Glycoprotein, Coronavirus
(chemistry, metabolism)
- Toll-Like Receptor 2
(metabolism)
- Toll-Like Receptor 4
(metabolism)
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