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. Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-β) and III (IFN-λ) interferons are host-produced antiviral cytokines. Prolonged IFN-α and IFN-β responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, thereby inducing localized antiviral immunity. In this work, we show that IFN signaling interferes with lung repair during influenza recovery in mice, with IFN-λ driving these effects most potently. IFN-induced protein p53 directly reduces epithelial proliferation and differentiation, which increases disease severity and susceptibility to bacterial superinfections. Thus, excessive or prolonged IFN production aggravates viral infection by impairing lung epithelial regeneration. Timing and duration are therefore critical parameters of endogenous IFN action and should be considered carefully for IFN therapeutic strategies against viral infections such as influenza and coronavirus disease 2019 (COVID-19).

中文翻译：

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I型和III型干扰素在病毒感染恢复期间破坏肺上皮修复

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 IFN (IFN-λ) 反应主要局限于粘膜表面，并且被认为在不驱动破坏性促炎反应的情况下提供抗病毒保护。因此，已提议将 IFN-λ 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。报告称，COVID-19 患者的发病率与肺中 I 型和 III 型 IFN 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 会导致肺上皮细胞受损，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（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。使这张照片复杂化的是，Hadjadj 等人。观察到来自重症和重症 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 的反应。这表明，与本地生产相比，干扰素的全身产生可能是有益的。这三项研究的结果表明，IFN 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 3 页。第 706 页，第 第 712 页，第 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。过多的细胞因子信号传导经常加剧呼吸道病毒感染期间的肺组织损伤。I 型（IFN-α 和 IFN-β）和 III 型（IFN-λ）干扰素是宿主产生的抗病毒细胞因子。延长的 IFN-α 和 IFN-β 反应可导致有害的促炎作用，而 IFN-λ 主要在上皮细胞中发出信号，从而诱导局部抗病毒免疫。在这项工作中，我们表明，在小鼠流感恢复期间，IFN 信号会干扰肺修复，而 IFN-λ 最有效地驱动了这些影响。IFN 诱导的蛋白 p53 直接减少上皮增殖和分化，从而增加疾病严重程度和对细菌重复感染的易感性。因此，过度或长时间的 IFN 产生会通过损害肺上皮再生来加重病毒感染。因此，时间和持续时间是内源性 IFN 作用的关键参数，在针对病毒感染（如 2019 年流感和冠状病毒病 (COVID-19)）的 IFN 治疗策略中应仔细考虑。这会增加疾病的严重程度和对细菌重复感染的易感性。因此，过度或长时间的 IFN 产生会通过损害肺上皮再生来加重病毒感染。因此，时间和持续时间是内源性 IFN 作用的关键参数，在针对病毒感染（如 2019 年流感和冠状病毒病 (COVID-19)）的 IFN 治疗策略中应仔细考虑。这会增加疾病的严重程度和对细菌重复感染的易感性。因此，过度或长时间的 IFN 产生会通过损害肺上皮再生来加重病毒感染。因此，时间和持续时间是内源性 IFN 作用的关键参数，在针对病毒感染（如 2019 年流感和冠状病毒病 (COVID-19)）的 IFN 治疗策略中应仔细考虑。