Rhinovirus-induced Human Lung Tissue Responses Mimic Chronic Obstructive Pulmonary Disease and Asthma Gene Signatures
Human rhinovirus (RV) is a major risk factor for chronic obstructive pulmonary disease (COPD) and asthma exacerbations. The exploration of RV pathogenesis has been hampered by a lack of disease-relevant model systems. We performed a detailed characterization of host responses to RV infection in human lung tissue ex vivo and investigated whether these responses are disease relevant for patients with COPD and asthma. In addition, impact of the viral replication inhibitor rupintrivir was evaluated. Human precision-cut lung slices (PCLS) were infected with RV1B with or without rupintrivir. At Days 1 and 3 after infection, RV tissue localization, tissue viability, and viral load were determined. To characterize host responses to infection, mediator and whole genome analyses were performed. RV successfully replicated in PCLS airway epithelial cells and induced both antiviral and proinflammatory cytokines such as IFNα2a, CXCL10, CXCL11, IFN-γ, TNFα, and CCL5. Genomic analyses revealed that RV not only induced antiviral immune responses but also triggered changes in epithelial cell-associated pathways. Strikingly, the RV response in PCLS was reflective of gene expression changes described in patients with COPD and asthma. Although RV-induced host immune responses were abrogated by rupintrivir, RV-triggered epithelial processes were largely refractory to antiviral treatment. Detailed analysis of RV-infected human PCLS and comparison with gene signatures of patients with COPD and asthma revealed that the human RV PCLS model represents disease-relevant biological mechanisms that can be partially inhibited by a well-known antiviral compound and provide an outstanding opportunity to evaluate novel therapeutics.
| Errataetall: |
CommentIn: Am J Respir Cell Mol Biol. 2021 Nov;65(5):471-472. - PMID 34348085 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:65 |
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| Enthalten in: |
American journal of respiratory cell and molecular biology - 65(2021), 5 vom: 08. Nov., Seite 544-554 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wronski, Sabine [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.11.2021 Date Revised 07.12.2021 published: Print CommentIn: Am J Respir Cell Mol Biol. 2021 Nov;65(5):471-472. - PMID 34348085 Citation Status MEDLINE |
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| doi: |
10.1165/rcmb.2020-0337OC |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM327288647 |
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| 500 | |a CommentIn: Am J Respir Cell Mol Biol. 2021 Nov;65(5):471-472. - PMID 34348085 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Human rhinovirus (RV) is a major risk factor for chronic obstructive pulmonary disease (COPD) and asthma exacerbations. The exploration of RV pathogenesis has been hampered by a lack of disease-relevant model systems. We performed a detailed characterization of host responses to RV infection in human lung tissue ex vivo and investigated whether these responses are disease relevant for patients with COPD and asthma. In addition, impact of the viral replication inhibitor rupintrivir was evaluated. Human precision-cut lung slices (PCLS) were infected with RV1B with or without rupintrivir. At Days 1 and 3 after infection, RV tissue localization, tissue viability, and viral load were determined. To characterize host responses to infection, mediator and whole genome analyses were performed. RV successfully replicated in PCLS airway epithelial cells and induced both antiviral and proinflammatory cytokines such as IFNα2a, CXCL10, CXCL11, IFN-γ, TNFα, and CCL5. Genomic analyses revealed that RV not only induced antiviral immune responses but also triggered changes in epithelial cell-associated pathways. Strikingly, the RV response in PCLS was reflective of gene expression changes described in patients with COPD and asthma. Although RV-induced host immune responses were abrogated by rupintrivir, RV-triggered epithelial processes were largely refractory to antiviral treatment. Detailed analysis of RV-infected human PCLS and comparison with gene signatures of patients with COPD and asthma revealed that the human RV PCLS model represents disease-relevant biological mechanisms that can be partially inhibited by a well-known antiviral compound and provide an outstanding opportunity to evaluate novel therapeutics | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Beinke, Soren |e verfasserin |4 aut | |
| 700 | 1 | |a Obernolte, Helena |e verfasserin |4 aut | |
| 700 | 1 | |a Belyaev, Nikolai N |e verfasserin |4 aut | |
| 700 | 1 | |a Saunders, Ken A |e verfasserin |4 aut | |
| 700 | 1 | |a Lennon, Mark G |e verfasserin |4 aut | |
| 700 | 1 | |a Schaudien, Dirk |e verfasserin |4 aut | |
| 700 | 1 | |a Braubach, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Jonigk, Danny |e verfasserin |4 aut | |
| 700 | 1 | |a Warnecke, Gregor |e verfasserin |4 aut | |
| 700 | 1 | |a Zardo, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Fieguth, Hans-Gerd |e verfasserin |4 aut | |
| 700 | 1 | |a Wilkens, Ludwig |e verfasserin |4 aut | |
| 700 | 1 | |a Braun, Armin |e verfasserin |4 aut | |
| 700 | 1 | |a Hessel, Edith M |e verfasserin |4 aut | |
| 700 | 1 | |a Sewald, Katherina |e verfasserin |4 aut | |
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