Enteric viruses including hepatitis E virus (HEV), human norovirus (HuNV), and rotavirus are causing global health issues. The host interferon (IFN) response constitutes the first-line defense against viral infections. Melanoma Differentiation-Associated protein 5 (MDA5) is an important cytoplasmic receptor sensing viral infection to trigger IFN production, and on the other hand it is also an IFN-stimulated gene (ISG). In this study, we investigated the effects and mode-of-action of MDA5 on the infection of enteric viruses. We found that MDA5 potently inhibited HEV, HuNV and rotavirus replication in multiple cell models. Overexpression of MDA5 induced transcription of important antiviral ISGs through IFN-like response, without triggering of functional IFN production. Interestingly, MDA5 activates the expression and phosphorylation of STAT1, which is a central component of the JAK-STAT cascade and a hallmark of antiviral IFN response. However, genetic silencing of STAT1 or pharmacological inhibition of the JAK-STAT cascade only partially attenuated the induction of ISG transcription and the antiviral function of MDA5. Thus, we have demonstrated that MDA5 effectively inhibits HEV, HuNV and rotavirus replication through provoking a non-canonical IFN-like response, which is partially dependent on JAK-STAT cascade.

中文翻译：

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MDA5通过部分通过JAK-STAT级联诱导干扰素样反应来抵抗肠道病毒。

肠病毒包括戊型肝炎病毒（HEV），人诺如病毒（HuNV）和轮状病毒正在引起全球健康问题。宿主干扰素（IFN）反应构成了抵抗病毒感染的一线防御。黑色素瘤分化相关蛋白5（MDA5）是一种重要的细胞质受体，可感知病毒感染以触发IFN的产生，另一方面，它也是IFN刺激的基因（ISG）。在这项研究中，我们调查了MDA5对肠道病毒感染的影响和作用方式。我们发现MDA5在多种细胞模型中有效抑制HEV，HuNV和轮状病毒复制。MDA5的过表达通过类似IFN的反应诱导重要的抗病毒ISG的转录，而不触发功能性IFN的产生。有趣的是，MDA5激活STAT1的表达和磷酸化，它是JAK-STAT级联的重要组成部分，也是抗病毒IFN反应的标志。但是，STAT1的基因沉默或JAK-STAT级联的药理抑制仅部分减弱了ISG转录的诱导和MDA5的抗病毒功能。因此，我们证明了MDA5通过引起非典型的IFN样应答（部分依赖于JAK-STAT级联反应）有效抑制HEV，HuNV和轮状病毒复制。