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
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DOI：
10.1164/rccm.201901-0214oc
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发表时间：
2020-01-01
影响因子：
24.7
通讯作者：
Wilkinson, Tom
中科院分区：
文献类型：
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作者：
Watson, Alastair;Spalluto, C. Mirella;Wilkinson, Tom
基本原理：病毒感染是哮喘和慢性阻塞性肺疾病（COPD）患者病情加重和临床负担的主要驱动因素。IFN-β是对病毒感染的先天免疫应答的关键组分。迄今为止，吸入性IFN-β治疗的研究尚未证明对哮喘急性发作有显著效果。目的：研究外源性IFN-β活性的动力学，以了解这种潜在抗病毒治疗的未来临床适应症。方法：单核细胞衍生的巨噬细胞（MDM），肺泡巨噬细胞，和原代支气管上皮细胞（PBEC）分离自健康对照受试者和COPD患者，并在IFN-γ之前或之后感染流感病毒。β刺激使用流式细胞术通过核蛋白1阳性细胞的百分比测量感染水平。通过定量PCR测量病毒RNA脱落和IFN刺激的基因表达。测量和主要结果：在感染前，而不是感染后，将IFN-β添加到MDM、肺泡巨噬细胞和PBEC中，分别使核蛋白1阳性细胞的百分比减少85%、56%和66%（P < 0.05）。在去除IFN-β后，感染抑制持续24小时，尽管在MDM中减少了1周，在PBEC中减少了72小时，但仍维持感染抑制;这在健康对照受试者和COPD患者之间相似。IFN-β没有诱导炎症细胞因子的生产MDM或PBECs，但减少流感诱导的IL-1 β生产PBECs.Conclusions：在体外建模的IFN-β动力学突出了间歇性预防剂量的外源性IFN-β调节病毒感染的潜力。这提供了重要的见解，以帮助未来的设计IFN-β在哮喘和COPD的临床试验。
Rationale: Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and chronic obstructive pulmonary disease (COPD). IFN-beta is a key component of the innate immune response to viral infection. To date, studies of inhaled IFN-beta treatment have not demonstrated a significant effect on asthma exacerbations.Objectives: The dynamics of exogenous IFN-beta 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-beta 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-beta 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-beta 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-beta did not induce inflammatory cytokine production by MDMs or PBECs but reduced influenza-induced IL-1 beta production by PBECs.Conclusions: In vitro modeling of IFN-beta dynamics highlights the potential for intermittent prophylactic doses of exogenous IFN-beta to modulate viral infection. This provides important insights to aid the future design of clinical trials of IFN-beta in asthma and COPD.