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. Viral infections of the lower respiratory tract are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. In this study, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report that IFN-λ is present in the lower, but not upper, airways of patients with coronavirus disease 2019 (COVID-19). In mice, we demonstrate that IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in clinical practice against endemic viruses, such as influenza virus as well as the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

中文翻译：

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III型干扰素在病毒识别后破坏肺上皮屏障

干扰素干扰肺修复 干扰素 (IFN) 是抗病毒免疫的核心。病毒识别引发 IFN 产生，进而触发 IFN 刺激基因 (ISG) 的转录，这些基因参与各种抗病毒功能。I 型 IFN（IFN-α 和 IFN-β）广泛表达，可在病毒感染期间导致免疫病理学。相比之下，III 型干扰素 (IFN-λ) 反应主要限于粘膜表面，被认为可以提供抗病毒保护，而不会驱动破坏性的促炎反应。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剂（参见 Grajales-Reyes 和 Colonna 的观点）。布罗吉等人。报告 COVID-19 患者的发病率与肺中 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 会导致肺上皮损伤，从而增加对致命细菌重复感染的易感性。同样，使用流感感染的小鼠模型，Major 等人。发现 IFN 信号传导（尤其是 IFN-λ）通过诱导 p53 和抑制上皮增殖和分化来阻碍肺修复。使这幅画复杂化，Hadjadj 等人。观察到来自重症和危重 COVID-19 患者的外周血免疫细胞减少了 I 型干扰素，增强了促炎性白细胞介素 6 和肿瘤坏死因子 α 激发的反应。这表明，与本地生产相比，干扰素的全身性产生可能是有益的。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，这个问题 p。706 页。712 页。718; 另见第 626 干扰素可以增强和减轻呼吸道病毒感染的严重程度。下呼吸道的病毒感染是导致死亡的主要原因。越来越多的证据表明，大多数严重病例的特征是异常的免疫反应，不依赖于病毒负荷。在这项研究中，我们评估了 III 型干扰素 (IFN-λ) 如何促进 RNA 病毒诱导的发病机制。我们报告 IFN-λ 存在于 2019 年冠状病毒病 (COVID-19) 患者的下气道中，但不存在于上气道中。在小鼠中，我们证明肺树突细胞响应合成病毒 RNA 产生的 IFN-λ 诱导屏障损伤，导致对致命细菌重复感染的易感性。这些发现为重新思考 IFN-λ 的病理生理学作用及其在针对地方性病毒（如流感病毒）以及新出现的严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）感染的临床实践中的可能用途提供了强有力的理由。