Interferons interfere with lung repair Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections. Science, this issue p. 706, p. 712, p. 718; see also p. 626 Interferons can both enhance and abate the severity of respiratory viral infections. Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor–κB and characterized by increased tumor necrosis factor–α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

中文翻译：

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重症 COVID-19 患者 I 型干扰素活性和炎症反应受损


干扰素干扰肺部修复 干扰素 (IFN) 是抗病毒免疫的核心。病毒识别会引发 IFN 产生，进而触发 IFN 刺激基因 (ISG) 的转录，从而发挥各种抗病毒功能。 I 型干扰素（IFN-α 和 IFN-β）广泛表达，可导致病毒感染期间的免疫病理学变化。相比之下，III 型干扰素 (IFN-λ) 反应主要局限于粘膜表面，被认为可以提供抗病毒保护，而不会引发破坏性的促炎反应。因此，IFN-λ 已被提议作为 2019 年冠状病毒病 (COVID-19) 和其他此类病毒性呼吸道疾病的治疗药物（参见 Grajales-Reyes 和 Colonna 的观点）。布罗吉等人。报告称，COVID-19 患者的发病率与肺部 I 型和 III 型干扰素的高表达相关。此外，暴露于合成病毒RNA的小鼠肺部树突状细胞分泌的IFN-λ会对肺上皮造成损害，从而增加对致命细菌重复感染的易感性。同样，Major 等人使用流感感染的小鼠模型。发现 IFN 信号传导（尤其是 IFN-λ）通过诱导 p53 并抑制上皮增殖和分化来阻碍肺修复。 Hadjadj 等人使这一情况变得复杂。观察到，来自重症和危重症 COVID-19 患者的外周血免疫细胞减少了 I 型 IFN，并增强了促炎性白细胞介素 6 和肿瘤坏死因子 α 的反应。这表明，与局部生产相比，系统性生产干扰素可能是有益的。 这三项研究的结果表明，干扰素暴露的位置、时间和持续时间是病毒性呼吸道感染治疗成功或失败的关键参数。科学，本期第 14 页。 706，p。 712，p。 718;另见 p. 626 干扰素既可以增强也可以减轻呼吸道病毒感染的严重程度。 2019 年冠状病毒病 (COVID-19) 的特点是疾病进展的不同模式，表明宿主免疫反应不同。我们对 50 名患有不同疾病严重程度的 COVID-19 患者进行了综合免疫分析。在重症和危重症患者中观察到了独特的表型，包括高度受损的干扰素（IFN）I型反应（其特征是没有IFN-β和低IFN-α产生和活性），这与持续的血液病毒载量和炎症反应加剧。炎症部分由转录因子核因子-κB 驱动，其特征是肿瘤坏死因子-α 和白细胞介素 6 的产生和信号传导增加。这些数据表明，血液中 I 型 IFN 缺乏可能是严重 COVID-19 的一个标志，并为联合治疗方法提供了依据。