tetano
Editor, Senior Moderator
Am J Respir Crit Care Med. 2019 Aug 28. doi: 10.1164/rccm.201901-0214OC. [Epub ahead of print]
[h=1]Dynamics of IFN-β Responses During Respiratory Viral Infection: Insights for Therapeutic Strategies.[/h] Watson A[SUP]1[/SUP], Spalluto CM[SUP]1,[/SUP][SUP]2[/SUP], McCrae C[SUP]3,[/SUP][SUP]4[/SUP], Cellura D[SUP]1[/SUP], Burke H[SUP]1,[/SUP][SUP]5[/SUP], Cunoosamy D[SUP]3[/SUP], Freeman A[SUP]1,[/SUP][SUP]6[/SUP], Hicks A[SUP]5[/SUP], H?hn M[SUP]7[/SUP], Ostridge K[SUP]1,[/SUP][SUP]5[/SUP], Staples KJ[SUP]1,[/SUP][SUP]8[/SUP], Vaarala O[SUP]9[/SUP], Wilkinson T[SUP]1,[/SUP][SUP]10[/SUP].
[h=3]Author information[/h] 1 University of Southampton, Faculty of Medicine, Clinical & Experimental Sciences, Southampton, United Kingdom of Great Britain and Northern Ireland. 2 Wessex Investigational Sciences Hub, University of Southampton, Southampton, United Kingdom of Great Britain and Northern Ireland. 3 Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. 4 University of Gothenburg, Institute of Medicine, Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Gothenburg, Sweden. 5 University Hospital Southampton NHS Foundation Trust, 7425, NIHR Southampton Biomedical Research Centre, Southampton, United Kingdom of Great Britain and Northern Ireland. 6 University Hospital Southampton NHS Foundation Trust, NIHR Southampton Biomedical Research Centre, Southampton, United Kingdom of Great Britain and Northern Ireland. 7 Target & Translational Science, Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, Gothenburg, Sweden. 8 Wessex Investigational Sciences Hub, University of Southampton, Faculty of Medicine, Southampton, United Kingdom of Great Britain and Northern Ireland. 9 Respiratory, Inflammation and Autoimmunity, IMED Biotech Lung Immunity, AstraZeneca, Gothenburg, Sweden. 10 University Hospital Southampton NHS Foundation Trust, NIHR Southampton Biomedical Research Centre, Southampton, United Kingdom of Great Britain and Northern Ireland; t.wilkinson@soton.ac.uk.
[h=3]Abstract[/h] [h=4]RATIONALE:[/h] 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.
[h=4]OBJECTIVES:[/h] The dynamics of exogenous IFN-β activity were investigated to inform on future clinical indications for this potential anti-viral therapy.
[h=4]METHODS:[/h] Monocyte-derived macrophages (MDMs), alveolar macrophages 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.
[h=4]MAIN RESULTS:[/h] Adding IFN-β to MDMs, alveolar macrophages 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 24 h following removal of IFN-β and was maintained albeit reduced up to 1 week in MDMs and 72 h 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.
[h=4]CONCLUSIONS:[/h] 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.
[h=4]KEYWORDS:[/h] Innate Immunity, Respiratory Viruses, Exacerbation, Chronic Obstructive Pulmonary Disease.
PMID: 31461630 DOI: 10.1164/rccm.201901-0214OC
[h=1]Dynamics of IFN-β Responses During Respiratory Viral Infection: Insights for Therapeutic Strategies.[/h] Watson A[SUP]1[/SUP], Spalluto CM[SUP]1,[/SUP][SUP]2[/SUP], McCrae C[SUP]3,[/SUP][SUP]4[/SUP], Cellura D[SUP]1[/SUP], Burke H[SUP]1,[/SUP][SUP]5[/SUP], Cunoosamy D[SUP]3[/SUP], Freeman A[SUP]1,[/SUP][SUP]6[/SUP], Hicks A[SUP]5[/SUP], H?hn M[SUP]7[/SUP], Ostridge K[SUP]1,[/SUP][SUP]5[/SUP], Staples KJ[SUP]1,[/SUP][SUP]8[/SUP], Vaarala O[SUP]9[/SUP], Wilkinson T[SUP]1,[/SUP][SUP]10[/SUP].
[h=3]Author information[/h] 1 University of Southampton, Faculty of Medicine, Clinical & Experimental Sciences, Southampton, United Kingdom of Great Britain and Northern Ireland. 2 Wessex Investigational Sciences Hub, University of Southampton, Southampton, United Kingdom of Great Britain and Northern Ireland. 3 Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. 4 University of Gothenburg, Institute of Medicine, Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Gothenburg, Sweden. 5 University Hospital Southampton NHS Foundation Trust, 7425, NIHR Southampton Biomedical Research Centre, Southampton, United Kingdom of Great Britain and Northern Ireland. 6 University Hospital Southampton NHS Foundation Trust, NIHR Southampton Biomedical Research Centre, Southampton, United Kingdom of Great Britain and Northern Ireland. 7 Target & Translational Science, Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, Gothenburg, Sweden. 8 Wessex Investigational Sciences Hub, University of Southampton, Faculty of Medicine, Southampton, United Kingdom of Great Britain and Northern Ireland. 9 Respiratory, Inflammation and Autoimmunity, IMED Biotech Lung Immunity, AstraZeneca, Gothenburg, Sweden. 10 University Hospital Southampton NHS Foundation Trust, NIHR Southampton Biomedical Research Centre, Southampton, United Kingdom of Great Britain and Northern Ireland; t.wilkinson@soton.ac.uk.
[h=3]Abstract[/h] [h=4]RATIONALE:[/h] 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.
[h=4]OBJECTIVES:[/h] The dynamics of exogenous IFN-β activity were investigated to inform on future clinical indications for this potential anti-viral therapy.
[h=4]METHODS:[/h] Monocyte-derived macrophages (MDMs), alveolar macrophages 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.
[h=4]MAIN RESULTS:[/h] Adding IFN-β to MDMs, alveolar macrophages 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 24 h following removal of IFN-β and was maintained albeit reduced up to 1 week in MDMs and 72 h 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.
[h=4]CONCLUSIONS:[/h] 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.
[h=4]KEYWORDS:[/h] Innate Immunity, Respiratory Viruses, Exacerbation, Chronic Obstructive Pulmonary Disease.
PMID: 31461630 DOI: 10.1164/rccm.201901-0214OC