PMID- 34181859 OWN - NLM STAT- MEDLINE DCOM- 20211118 LR - 20211207 IS - 1535-4989 (Electronic) IS - 1044-1549 (Print) IS - 1044-1549 (Linking) VI - 65 IP - 5 DP - 2021 Nov TI - Rhinovirus-induced Human Lung Tissue Responses Mimic Chronic Obstructive Pulmonary Disease and Asthma Gene Signatures. PG - 544-554 LID - 10.1165/rcmb.2020-0337OC [doi] AB - 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 IFNalpha2a, CXCL10, CXCL11, IFN-gamma, TNFalpha, 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. FAU - Wronski, Sabine AU - Wronski S AUID- ORCID: 0000-0002-2332-226X AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Member of Fraunhofer International Consortium for Antiinfective Research, Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany. AD - Biomedical Research in End-Stage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany. FAU - Beinke, Soren AU - Beinke S AD - Research and Development, GlaxoSmithKline, Stevenage, United Kingdom. FAU - Obernolte, Helena AU - Obernolte H AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Member of Fraunhofer International Consortium for Antiinfective Research, Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany. AD - Biomedical Research in End-Stage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany. FAU - Belyaev, Nikolai N AU - Belyaev NN AD - Research and Development, GlaxoSmithKline, Stevenage, United Kingdom. FAU - Saunders, Ken A AU - Saunders KA AUID- ORCID: 0000-0002-9284-1100 AD - Research and Development, GlaxoSmithKline, Stevenage, United Kingdom. FAU - Lennon, Mark G AU - Lennon MG AUID- ORCID: 0000-0001-7379-3302 AD - Research and Development, GlaxoSmithKline, Stevenage, United Kingdom. FAU - Schaudien, Dirk AU - Schaudien D AUID- ORCID: 0000-0001-7398-7262 AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Member of Fraunhofer International Consortium for Antiinfective Research, Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany. AD - Biomedical Research in End-Stage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany. FAU - Braubach, Peter AU - Braubach P AUID- ORCID: 0000-0003-3673-7779 AD - Biomedical Research in End-Stage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany. AD - Department of Pathology, and. FAU - Jonigk, Danny AU - Jonigk D AUID- ORCID: 0000-0002-5251-2281 AD - Biomedical Research in End-Stage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany. AD - Department of Pathology, and. FAU - Warnecke, Gregor AU - Warnecke G AD - Biomedical Research in End-Stage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany. AD - Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany; and. FAU - Zardo, Patrick AU - Zardo P AD - Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany; and. FAU - Fieguth, Hans-Gerd AU - Fieguth HG AD - Klinikum Region Hannover Clinics, Hannover, Germany. FAU - Wilkens, Ludwig AU - Wilkens L AD - Klinikum Region Hannover Clinics, Hannover, Germany. FAU - Braun, Armin AU - Braun A AUID- ORCID: 0000-0002-1142-1463 AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Member of Fraunhofer International Consortium for Antiinfective Research, Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany. AD - Biomedical Research in End-Stage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany. FAU - Hessel, Edith M AU - Hessel EM AD - Research and Development, GlaxoSmithKline, Stevenage, United Kingdom. FAU - Sewald, Katherina AU - Sewald K AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Member of Fraunhofer International Consortium for Antiinfective Research, Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany. AD - Biomedical Research in End-Stage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Am J Respir Cell Mol Biol JT - American journal of respiratory cell and molecular biology JID - 8917225 RN - 0 (Antiviral Agents) RN - 0 (Isoxazoles) RN - 0 (Pyrrolidinones) RN - 47E5O17Y3R (Phenylalanine) RN - HG18B9YRS7 (Valine) RN - RGE5K1Q5QW (rupintrivir) SB - IM CIN - Am J Respir Cell Mol Biol. 2021 Nov;65(5):471-472. PMID: 34348085 MH - Aged MH - Antiviral Agents/pharmacology MH - Asthma/*genetics/pathology MH - Bronchi/pathology/physiology MH - Epithelial Cells/pathology/virology MH - Female MH - Gene Expression Profiling MH - Genome, Human MH - Host-Pathogen Interactions/*genetics MH - Humans MH - Isoxazoles/pharmacology MH - Lung/physiology/*virology MH - Male MH - Middle Aged MH - Phenylalanine/analogs & derivatives/pharmacology MH - Picornaviridae Infections/drug therapy/*genetics/pathology MH - Pulmonary Disease, Chronic Obstructive/*genetics/pathology MH - Pyrrolidinones/pharmacology MH - Rhinovirus/pathogenicity MH - Valine/analogs & derivatives/pharmacology PMC - PMC8641849 OTO - NOTNLM OT - COPD OT - asthma OT - epithelial response OT - human lung OT - rhinovirus EDAT- 2021/06/29 06:00 MHDA- 2021/11/19 06:00 PMCR- 2021/03/30 CRDT- 2021/06/28 20:10 PHST- 2021/06/29 06:00 [pubmed] PHST- 2021/11/19 06:00 [medline] PHST- 2021/06/28 20:10 [entrez] PHST- 2021/03/30 00:00 [pmc-release] AID - 10.1165/rcmb.2020-0337OC [doi] PST - ppublish SO - Am J Respir Cell Mol Biol. 2021 Nov;65(5):544-554. doi: 10.1165/rcmb.2020-0337OC.