Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness
Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness
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DOI：
10.1016/j.immuni.2017.04.025
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发表时间：
2017-05-16
期刊：
影响因子：
32.4
通讯作者：
Andreakos, Evangelos
中科院分区：
文献类型：
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作者：
Galani, Ioanna E.;Triantafyllia, Vasiliki;Andreakos, Evangelos
Lambda干扰素（IFN Lambda s）或III型IFN与I型IFN具有同源性、表达模式、信号级联和抗病毒功能。这使得他们独特的非冗余角色变得更加复杂。通过对小鼠流感病毒感染的系统研究，我们在此表明IFN lambda s是第一个产生的IFN，它作用于上皮屏障，抑制初始病毒传播而不激活炎症。如果感染进展，I型干扰素开始发挥作用，增强病毒耐药性，诱导对抗感染所必需的促炎反应，但会引起免疫病理。其核心是中性粒细胞，它对两种细胞因子都有反应，上调抗菌功能，但仅对I型ifn表现出促炎激活。因此，Ifnlr1（-/-）小鼠表现出增强的I型IFN产生、中性粒细胞增多、肺损伤和致死率，而治疗性给药PEG-IFN lambda可有效抑制这些作用。因此，IFN在不损害宿主健康的情况下构成肺部抗病毒防御的前线。
Lambda interferons (IFN lambda s) or type III IFNs share homology, expression patterns, signaling cascades, and antiviral functions with type I IFNs. This has complicated the unwinding of their unique non-redundant roles. Through the systematic study of influenza virus infection in mice, we herein show that IFN lambda s are the first IFNs produced that act at the epithelial barrier to suppress initial viral spread without activating inflammation. If infection progresses, type I IFNs come into play to enhance viral resistance and induce pro-inflammatory responses essential for confronting infection but causing immunopathology. Central to this are neutrophils which respond to both cytokines to upregulate antimicrobial functions but exhibit pro-inflammatory activation only to type I IFNs. Accordingly, Ifnlr1(-/-) mice display enhanced type I IFN production, neutrophilia, lung injury, and lethality, while therapeutic administration of PEG-IFN lambda potently suppresses these effects. IFN lambda s therefore constitute the front line of antiviral defense in the lung without compromising host fitness.