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Dynamics of IFN-β responses during respiratory viral infection: insights for therapeutic strategies

Dynamics of IFN-β responses during respiratory viral infection: insights for therapeutic strategies
Dynamics of IFN-β responses during respiratory viral infection: insights for therapeutic strategies
RATIONALE: Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and COPD. IFN-β is a key component of the innate immune response to viral infection. To date studies of inhaled IFN-β treatment have not demonstrated a significant effect on asthma exacerbations. OBJECTIVES: The dynamics of exogenous IFN-β activity were investigated to inform on future clinical indications for this potential anti-viral therapy. METHODS: Monocyte-derived macrophages (MDMs), alveolar macrophages (AMs) and primary bronchial epithelial cells (PBECs) were isolated from healthy controls and COPD patients and infected with influenza virus either prior to or after IFN-β stimulation. Infection levels were measured by % nucleoprotein 1 positive (NP1+) cells using flow cytometry. Viral RNA shedding and interferon stimulated gene expression were measured by qPCR. Production of inflammatory cytokines was measured using MSD. MEASUREMENTS AND MAIN RESULTS: Adding IFN-β to MDMs, AMs and PBECs prior to, but not after, infection reduced %NP1+ cells by 85%, 56% and 66%, respectively (p<0.05). Inhibition of infection lasted for 24h following removal of IFN-β and was maintained albeit reduced up to 1 week in MDMs and 72h in PBECs; this was similar between health and COPD. IFN-β did not induce inflammatory cytokine production by MDMs or PBECs but reduced influenza-induced IL-1β production by PBECs. CONCLUSIONS: In vitro modelling of IFN-β dynamics highlights the potential for intermittent prophylactic doses of exogenous IFN-β to modulate viral infection. This provides important insights to aid the future design of clinical trials of IFN-β in asthma and COPD.
Chronic obstructive pulmonary disease, Exacerbation, Innate immunity, Respiratory viruses
1073-449X
83-94
Watson, Alastair
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Spalluto, C. Mirella
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McCrae, Christopher
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Cellura, Doriana
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Burke, Hannah
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Cunoosamy, Danen
ea10b74c-a759-4a17-b71e-e6f20bdd6274
Freeman, Anna
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Hicks, Alex
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Huhn, Michael
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Ostridge, Kristoffer
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Staples, Karl J.
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Vaarala, Outi
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Wilkinson, Tom
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Watson, Alastair
9eb79329-8d32-4ed4-b8b9-d720883e8042
Spalluto, C. Mirella
6802ad50-bc38-404f-9a19-40916425183b
McCrae, Christopher
ff867925-ff4c-4cd0-bfb5-5e639e66b464
Cellura, Doriana
e4cffc4c-0e12-40e7-ad13-e90e3fb55332
Burke, Hannah
a9bb9391-4704-4584-aeb7-e69fe0acbdb8
Cunoosamy, Danen
ea10b74c-a759-4a17-b71e-e6f20bdd6274
Freeman, Anna
3d83f907-e7ce-4649-a018-a7a31b19f934
Hicks, Alex
d8d07898-d1ba-4428-b884-f929b65ae9ea
Huhn, Michael
dd672678-5f28-4928-b72f-fc73c11fa151
Ostridge, Kristoffer
d2271bae-b078-4390-8919-8f8c0e20542c
Staples, Karl J.
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Vaarala, Outi
35ea8119-e804-402c-bb79-cfac625e71f5
Wilkinson, Tom
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Watson, Alastair, Spalluto, C. Mirella, McCrae, Christopher, Cellura, Doriana, Burke, Hannah, Cunoosamy, Danen, Freeman, Anna, Hicks, Alex, Huhn, Michael, Ostridge, Kristoffer, Staples, Karl J., Vaarala, Outi and Wilkinson, Tom (2020) Dynamics of IFN-β responses during respiratory viral infection: insights for therapeutic strategies. American Journal of Respiratory and Critical Care Medicine, 201 (1), 83-94. (doi:10.1164/rccm.201901-0214OC).

Record type: Article

Abstract

RATIONALE: Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and COPD. IFN-β is a key component of the innate immune response to viral infection. To date studies of inhaled IFN-β treatment have not demonstrated a significant effect on asthma exacerbations. OBJECTIVES: The dynamics of exogenous IFN-β activity were investigated to inform on future clinical indications for this potential anti-viral therapy. METHODS: Monocyte-derived macrophages (MDMs), alveolar macrophages (AMs) and primary bronchial epithelial cells (PBECs) were isolated from healthy controls and COPD patients and infected with influenza virus either prior to or after IFN-β stimulation. Infection levels were measured by % nucleoprotein 1 positive (NP1+) cells using flow cytometry. Viral RNA shedding and interferon stimulated gene expression were measured by qPCR. Production of inflammatory cytokines was measured using MSD. MEASUREMENTS AND MAIN RESULTS: Adding IFN-β to MDMs, AMs and PBECs prior to, but not after, infection reduced %NP1+ cells by 85%, 56% and 66%, respectively (p<0.05). Inhibition of infection lasted for 24h following removal of IFN-β and was maintained albeit reduced up to 1 week in MDMs and 72h in PBECs; this was similar between health and COPD. IFN-β did not induce inflammatory cytokine production by MDMs or PBECs but reduced influenza-induced IL-1β production by PBECs. CONCLUSIONS: In vitro modelling of IFN-β dynamics highlights the potential for intermittent prophylactic doses of exogenous IFN-β to modulate viral infection. This provides important insights to aid the future design of clinical trials of IFN-β in asthma and COPD.

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Watson et al 2019 merged - Accepted Manuscript
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Accepted/In Press date: 19 August 2019
e-pub ahead of print date: 28 August 2019
Published date: 1 January 2020
Keywords: Chronic obstructive pulmonary disease, Exacerbation, Innate immunity, Respiratory viruses

Identifiers

Local EPrints ID: 433602
URI: http://eprints.soton.ac.uk/id/eprint/433602
ISSN: 1073-449X
PURE UUID: 41a5d821-1989-48ea-b1a9-786ed5b6e3c7
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457

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Date deposited: 28 Aug 2019 16:30
Last modified: 10 Jan 2022 02:52

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Contributors

Author: Alastair Watson
Author: C. Mirella Spalluto
Author: Christopher McCrae
Author: Doriana Cellura
Author: Hannah Burke
Author: Danen Cunoosamy
Author: Anna Freeman
Author: Alex Hicks
Author: Michael Huhn
Author: Kristoffer Ostridge
Author: Karl J. Staples ORCID iD
Author: Outi Vaarala
Author: Tom Wilkinson

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