IFN-λ determines the intestinal epithelial antiviral host defense
IFN-λ determines the intestinal epithelial antiviral host defense
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DOI：
10.1073/pnas.1100552108
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发表时间：
2011-05-10
影响因子：
11.1
通讯作者：
Hornef, Mathias W.
中科院分区：
文献类型：
--
作者：
Pott, Johanna;Mahlakoiv, Tanel;Hornef, Mathias W.
I型和III型IFN与不同的细胞表面受体结合，但诱导相同的信号转导途径，导致抗病毒宿主效应分子的表达。尽管III型IFN（IFN-λ）已被证明主要作用于粘膜器官，但体内感染研究未能归因于特定的非冗余功能。相反，观察到I型IFN的主要作用，这可以通过I型IFN受体的普遍表达来解释。在这里，我们比较分析了功能性IFN-λ和I型IFN受体信号转导在肠道轮状病毒感染的先天免疫应答中的作用，并在细胞水平上确定病毒复制和抗病毒基因表达。我们观察到，哺乳期和成年小鼠缺乏功能性受体的IFN-λ受损的控制口服轮状病毒感染，而动物缺乏功能性受体的I型IFN类似于野生型小鼠。使用Mx 1蛋白的积累作为标志物的IFN反应的个别细胞，我们表明，肠上皮细胞，这是主要的轮状病毒的靶细胞，强烈响应IFN-λ，但只有轻微的I型IFN在体内。用IFN-λ抑制轮状病毒在肠道中的复制，而用I型IFN的治疗是无效的。这些结果在鉴定IFN-λ在上皮抗病毒宿主防御中的关键作用方面是独特的。
Type I and type III IFNs bind to different cell-surface receptors but induce identical signal transduction pathways, leading to the expression of antiviral host effector molecules. Despite the fact that type III IFN (IFN-lambda) has been shown to predominantly act on mucosal organs, in vivo infection studies have failed to attribute a specific, nonredundant function. Instead, a predominant role of type I IFN was observed, which was explained by the ubiquitous expression of the type I IFN receptor. Here we comparatively analyzed the role of functional IFN-lambda and type I IFN receptor signaling in the innate immune response to intestinal rotavirus infection in vivo, and determined viral replication and antiviral gene expression on the cellular level. We observed that both suckling and adult mice lacking functional receptors for IFN-lambda were impaired in the control of oral rotavirus infection, whereas animals lacking functional receptors for type I IFN were similar to wild-type mice. Using Mx1 protein accumulation as marker for IFN responsiveness of individual cells, we demonstrate that intestinal epithelial cells, which are the prime target cells of rotavirus, strongly responded to IFN-lambda but only marginally to type I IFN in vivo. Systemic treatment of suckling mice with IFN-lambda repressed rotavirus replication in the gut, whereas treatment with type I IFN was not effective. These results are unique in identifying a critical role of IFN-lambda in the epithelial antiviral host defense.