Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
PLoS Pathog. 2011 Feb;7(2):e1001297. doi: 10.1371/journal.ppat.1001297. Epub 2011 Feb 17.
Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50-100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo.
登革热病毒（DENV）是一种通过蚊子传播的黄病毒，感染的症状范围从无症状到严重的登革出血热/登革休克综合征（DHF/DSS）。高病毒载量与疾病严重程度相关，I 型和 II 型干扰素（IFN）对于控制病毒复制至关重要。我们之前报道过 STAT1 缺陷型小鼠对 DENV 诱导的疾病具有抗性，但对于这种 STAT1 非依赖性保护机制知之甚少。为了确定 STAT1 非依赖性途径的分子基础，缺乏 STAT1、STAT2 或 STAT1 和 STAT2 的小鼠感染了一种强毒的小鼠适应株 DENV2。在感染的前 72 小时内，缺乏 STAT1 或 STAT2 的单缺陷型小鼠在血清、脾脏和其他内脏组织中的病毒 RNA 水平比野生型小鼠高 50-100 倍，但仍对 DENV 诱导的死亡具有抗性。相比之下，双缺陷型小鼠表现出以前在 I 型和 II 型 IFN 受体敲除小鼠（AG129）中观察到的早期死亡表型，表明 STAT2 是 STAT1 非依赖性宿主防御机制的介导者。进一步的研究表明，这种依赖于 STAT2 的 STAT1 非依赖性机制需要 I 型 IFN 受体，并有助于 I 型 IFN 表达的自分泌放大。在 DENV 感染后检查脾脏和骨髓来源的巨噬细胞中的基因表达表明，即使在缺乏 STAT1 的情况下，依赖于 STAT2 的途径也可以诱导一组干扰素刺激基因的转录。总的来说，这些结果通过鉴定体内 DENV 感染后依赖于 STAT2 的功能性 I 型 IFN/STAT2 信号通路，有助于阐明针对病毒的了解甚少的 STAT1 非依赖性宿主防御机制的性质。
