Alastair Watson1,2, C Mirella Spalluto1,2, Christopher McCrae3, Doriana Cellura1, Hannah Burke1,2, Danen Cunoosamy4, Anna Freeman1,2, Alex Hicks1,2, Michael Hühn4, Kristoffer Ostridge1,2,5, Karl J Staples1,2, Outi Vaarala3, Tom Wilkinson1,2. 1. Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, and. 2. NIHR Southampton Biomedical Research Centre, Southampton Centre for Biomedical Research, Southampton General Hospital, Southampton, UK. 3. Bioscience, Research and Early Development-Respiratory, Inflammation and Autoimmunity, R&D BioPharmaceuticals, AstraZeneca, Gaithersburg, Maryland. 4. Translational Science and Experimental Medicine, and. 5. Clinical Development, Research and Early Development-Respiratory, Inflammation and Autoimmunity, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden.
Abstract
Rationale: Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and chronic obstructive pulmonary disease (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 antiviral therapy. Methods: Monocyte-derived macrophages (MDMs), alveolar macrophages, and primary bronchial epithelial cells (PBECs) were isolated from healthy control subjects and patients with COPD and infected with influenza virus either prior to or after IFN-β stimulation. Infection levels were measured by the percentage of nucleoprotein 1-positive cells using flow cytometry. Viral RNA shedding and IFN-stimulated gene expression were measured by quantitative PCR. Production of inflammatory cytokines was measured using MSD.Measurements and Main Results: Adding IFN-β to MDMs, alveolar macrophages, and PBECs prior to, but not after, infection reduced the percentage of nucleoprotein 1-positive cells by 85, 56, and 66%, respectively (P < 0.05). Inhibition of infection lasted for 24 hours after removal of IFN-β and was maintained albeit reduced up to 1 week in MDMs and 72 hours in PBECs; this was similar between healthy control subjects and patients with 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 modeling 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.
Rationale: Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and chronic obstructive pulmonary disease (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 antiviral therapy. Methods: Monocyte-derived macrophages (MDMs), alveolar macrophages, and primary bronchial epithelial cells (PBECs) were isolated from healthy control subjects and patients with COPD and infected with influenza virus either prior to or after IFN-β stimulation. Infection levels were measured by the percentage of nucleoprotein 1-positive cells using flow cytometry. Viral RNA shedding and IFN-stimulated gene expression were measured by quantitative PCR. Production of inflammatory cytokines was measured using MSD.Measurements and Main Results: Adding IFN-β to MDMs, alveolar macrophages, and PBECs prior to, but not after, infection reduced the percentage of nucleoprotein 1-positive cells by 85, 56, and 66%, respectively (P < 0.05). Inhibition of infection lasted for 24 hours after removal of IFN-β and was maintained albeit reduced up to 1 week in MDMs and 72 hours in PBECs; this was similar between healthy control subjects and patients with 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 modeling 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.
Authors: Lisa Öberg; Bastian Angermann; Alastair Watson; C Mirella Spalluto; Michael Hühn; Hannah Burke; Doriana Cellura; Anna Freeman; Daniel Muthas; Damla Etal; Graham Belfield; Fredrik Karlsson; Karl Nordström; Kris Ostridge; Karl J Staples; Tom Wilkinson Journal: Respir Res Date: 2021-05-29
Authors: Li She; Hamad H Alanazi; Liping Yan; Edward G Brooks; Peter H Dube; Yan Xiang; Fushun Zhang; Yilun Sun; Yong Liu; Xin Zhang; Xiao-Dong Li Journal: PLoS One Date: 2020-07-30 Impact factor: 3.240
Authors: Anna T Freeman; David Hill; Colin Newell; Helen Moyses; Adnan Azim; Deborah Knight; Laura Presland; Matthew Harvey; Hans Michael Haitchi; Alastair Watson; Karl J Staples; Ramesh J Kurukulaaratchy; Tom M A Wilkinson Journal: Asthma Res Pract Date: 2020-06-09