Relative timing of type I interferon response and virus replication determines disease outcome during MERS-CoV infection

Type 1 interferons (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1-day post infection (before virus titers peak) protected mice from lethal infection, despite a decrease in ISG (interferon stimulated gene) and inflammatory cytokine gene expression. In contrast, delayed IFN-I treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocyte-macrophages and neutrophils into the lungs and enhanced pro-inflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sub-lethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-I or combination therapy may need to be used cautiously to treat virus infections in clinical settings. Overall design: Examination of gene expression in early and late IFN treated lungs after MERS-CoV infection.

I型干扰素（Type 1 interferons, IFN-I）通常可保护哺乳动物宿主抵御病毒感染，但在部分情境下，I型干扰素也可致病。鉴于其具备抗病毒保护活性，I型干扰素常被用于治疗尚无获批特异性药物或疫苗的病毒感染性疾病。中东呼吸综合征冠状病毒（Middle East respiratory syndrome-coronavirus, MERS-CoV）即属于此类疾病，但目前学界对I型干扰素在此类感染中的作用仍知之甚少。本研究证实，在中东呼吸综合征冠状病毒感染过程中，I型干扰素信号通路发挥保护作用。阻断I型干扰素信号通路会导致病毒清除延迟、中性粒细胞浸润增强以及MERS-CoV特异性T细胞应答受损。值得注意的是，在感染后1天内（病毒滴度达到峰值前）给予I型干扰素干预，可使小鼠免于致死性感染，尽管此时干扰素刺激基因（interferon stimulated gene, ISG）与炎症细胞因子的基因表达水平有所下调。与之形成对比的是，延迟给予I型干扰素治疗则无法有效抑制病毒复制，反而会增加单核细胞-巨噬细胞与中性粒细胞向肺部的浸润与活化，并上调促炎细胞因子的表达，进而在原本可耐受的亚致死感染中引发致死性肺炎。综上，本研究结果表明，至少在感染小鼠模型中，I型干扰素应答与病毒最大复制的相对时序是决定感染结局的关键因素。由此引申，临床治疗病毒感染性疾病时，需谨慎使用I型干扰素或其联合治疗方案。整体实验设计：检测中东呼吸综合征冠状病毒感染后，早期与延迟给予I型干扰素干预的小鼠肺部组织的基因表达情况。