Modulation of the unfolded protein response pathway as an antiviral approach in airway epithelial cells.

Schögler, Aline; Caliaro, Oliver Stephan; Brügger, Melanie; Oliveira Esteves, Blandina Isabel; Nita, Izabela Magdalena; Gazdhar, Amiq; Geiser, Thomas; Alves, Marco (2019). Modulation of the unfolded protein response pathway as an antiviral approach in airway epithelial cells. Antiviral research, 162, pp. 44-50. Elsevier 10.1016/j.antiviral.2018.12.007

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INTRODUCTION Rhinovirus (RV) infection is a major cause of cystic fibrosis (CF) lung morbidity with limited therapeutic options. Various diseases involving chronic inflammatory response and infection are associated with endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR), an adaptive response to maintain cellular homeostasis. Recent evidence suggests impaired ER stress response in CF airway epithelial cells, this might be a reason for recurrent viral infection in CF. Therefore, assuming that ER stress inducing drugs have antiviral properties, we evaluated the activation of the UPR by selected ER stress inducers as an approach to control virus replication in the CF bronchial epithelium. METHODS We assessed the levels of UPR markers, namely the glucose-regulated protein 78 (Grp78) and the C/EBP homologous protein (CHOP), in primary CF and control bronchial epithelial cells and in a CF and control bronchial epithelial cell line before and after infection with RV. The cells were also pretreated with ER stress-inducing drugs and RV replication and shedding was measured by quantitative RT-PCR and by a TCID assay, respectively. Cell death was assessed by a lactate dehydrogenate (LDH) activity test in supernatants. RESULTS We observed a significantly impaired induction of Grp78 and CHOP in CF compare to control cells following RV infection. The ER stress response could be significantly induced in CF cells by pharmacological ER stress inducers Brefeldin A, Tunicamycin, and Thapsigargin. The chemical induction of the UPR pathway prior to RV infection of CF and control cells reduced viral replication and shedding by up to two orders of magnitude and protected cells from RV-induced cell death. CONCLUSION RV infection causes an impaired activation of the UPR in CF cells. Rescue of the ER stress response by chemical ER stress inducers reduced significantly RV replication in CF cells. Thus, pharmacological modulation of the UPR might represent a strategy to control respiratory virus replication in the CF bronchial epithelium.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Pneumologie (Pädiatrie)
08 Faculty of Science > Departement of Chemistry and Biochemistry
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Clinical Microbiology
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Virology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Pneumology

UniBE Contributor:

Schögler, Aline; Brügger, Melanie; Oliveira Esteves, Blandina Isabel; Nita, Izabela Magdalena; Gazdhar, Amiq; Geiser, Thomas and Alves, Marco

Subjects:

600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry
600 Technology > 610 Medicine & health

ISSN:

0166-3542

Publisher:

Elsevier

Language:

English

Submitter:

Rahel Holderegger

Date Deposited:

07 Feb 2019 15:29

Last Modified:

14 Feb 2019 11:47

Publisher DOI:

10.1016/j.antiviral.2018.12.007

PubMed ID:

30550797

Uncontrolled Keywords:

Cystic fibrosis Endoplasmic reticulum stress Rhinovirus Unfolded protein response

BORIS DOI:

10.7892/boris.123209

URI:

https://boris.unibe.ch/id/eprint/123209

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