Impaired antiviral stress granule and IFN-β enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium

Alan C.Y. Hsu, Kristy Parsons, Fatemeh Moheimani, Darryl A. Knight, Philip M. Hansbro, Takashi Fujita, Peter A. Wark

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infections that result in exacerbations with exaggerated symptoms with increased mortality. The mechanisms underpinning this increased susceptibility to infection in COPD are unclear. In this study, we show that primary bronchial epithelial cells (pBECs) from subjects with COPD have impaired induction of type I IFN (IFN-β) and lead to heightened viral replication after influenza viral infection. COPD pBECs have reduced protein levels of protein kinase (PK) R and decreased formation of PKR-mediated antiviral stress granules, which are critical in initiating type I IFNinductions. In addition, reduced protein expression of p300 resulted in decreased activation of IFN regulatory factor 3 and subsequent formation of IFN-β enhanceosome in COPD pBECs. The decreased p300 induction was the result of enhanced levels of microRNA (miR)-132. Ectopic expression of PKR or miR-132 antagomiR alone failed to restore IFN-β induction, whereas cotreatment increased antiviral stress granule formation, induction of p300, and IFN-β in COPD pBECs. This study reveals that decreased induction of both PKR and p300 proteins contribute to impaired induction of IFN-β in COPD pBECs upon influenza infection.

Original languageEnglish
Pages (from-to)117-127
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume55
Issue number1
DOIs
Publication statusPublished - 1 Jul 2016

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Pulmonary diseases
Chronic Obstructive Pulmonary Disease
Human Influenza
Antiviral Agents
Epithelium
Epithelial Cells
Infection
Virus Diseases
MicroRNAs
Interferon Regulatory Factor-3
Proteins
Orthomyxoviridae
Protein Kinases
Lung Diseases
Viruses
Chemical activation
Lung
Mortality

Cite this

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title = "Impaired antiviral stress granule and IFN-β enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium",
abstract = "Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infections that result in exacerbations with exaggerated symptoms with increased mortality. The mechanisms underpinning this increased susceptibility to infection in COPD are unclear. In this study, we show that primary bronchial epithelial cells (pBECs) from subjects with COPD have impaired induction of type I IFN (IFN-β) and lead to heightened viral replication after influenza viral infection. COPD pBECs have reduced protein levels of protein kinase (PK) R and decreased formation of PKR-mediated antiviral stress granules, which are critical in initiating type I IFNinductions. In addition, reduced protein expression of p300 resulted in decreased activation of IFN regulatory factor 3 and subsequent formation of IFN-β enhanceosome in COPD pBECs. The decreased p300 induction was the result of enhanced levels of microRNA (miR)-132. Ectopic expression of PKR or miR-132 antagomiR alone failed to restore IFN-β induction, whereas cotreatment increased antiviral stress granule formation, induction of p300, and IFN-β in COPD pBECs. This study reveals that decreased induction of both PKR and p300 proteins contribute to impaired induction of IFN-β in COPD pBECs upon influenza infection.",
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Impaired antiviral stress granule and IFN-β enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium. / Hsu, Alan C.Y.; Parsons, Kristy; Moheimani, Fatemeh; Knight, Darryl A.; Hansbro, Philip M.; Fujita, Takashi; Wark, Peter A.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 55, No. 1, 01.07.2016, p. 117-127.

Research output: Contribution to journalArticleResearchpeer-review

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