García-Sastre A, Durbin R K, Zheng H, Palese P, Gertner R, Levy D E, Durbin J E
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Virol. 1998 Nov;72(11):8550-8. doi: 10.1128/JVI.72.11.8550-8558.1998.
We have studied the pathogenesis of influenza virus infection in mice that are unable to respond to type I or II interferons due to a targeted disruption of the STAT1 gene. STAT1-/- animals are 100-fold more sensitive to lethal infection with influenza A/WSN/33 virus than are their wild-type (WT) counterparts. Virus replicated only in the lungs of WT animals following intranasal (i.n.) virus inoculation, while STAT1-/- mice developed a fulminant systemic influenza virus infection following either i.n. or intraperitoneal inoculation. We investigated the mechanism underlying this altered virus tropism by comparing levels of virus replication in fibroblast cell lines and murine embryonic fibroblasts derived from WT mice, STAT-/- mice, and mice lacking gamma interferon (IFNgamma-/- mice) or the IFN-alpha receptor (IFNalphaR-/- mice). Influenza A/WSN/33 virus replicates to high titers in STAT1-/- or IFNalphaR-/- fibroblasts, while cells derived from WT or IFNgamma-/- animals are resistant to influenza virus infection. Immunofluorescence studies using WT fibroblast cell lines demonstrated that only a small subpopulation of WT cells can be infected and that in the few infected WT cells, virus replication is aborted at an early, nuclear phase. In all organs examined except the lung, influenza A WSN/33 virus infection is apparently prevented by an intact type I interferon response. Our results demonstrate that type I interferon plays an important role in determining the pathogenicity and tissue restriction of influenza A/WSN/33 virus in vivo and in vitro.
我们研究了因STAT1基因靶向破坏而无法对I型或II型干扰素作出反应的小鼠中流感病毒感染的发病机制。与野生型（WT）对照相比，STAT1基因敲除（STAT1-/-）动物对甲型流感病毒A/WSN/33的致死性感染的敏感性高100倍。经鼻内（i.n.）接种病毒后，病毒仅在野生型动物的肺中复制，而STAT1-/-小鼠经鼻内或腹腔接种后均会发生暴发性全身性流感病毒感染。我们通过比较来自野生型小鼠、STAT1-/-小鼠、缺乏γ干扰素的小鼠（IFNγ-/-小鼠）或缺乏I型干扰素受体的小鼠（IFNαR-/-小鼠）的成纤维细胞系和小鼠胚胎成纤维细胞中的病毒复制水平，研究了这种病毒嗜性改变的潜在机制。甲型流感病毒A/WSN/33在STAT1-/-或IFNαR-/-成纤维细胞中可复制至高滴度，而来自野生型或IFNγ-/-动物的细胞对流感病毒感染具有抗性。使用野生型成纤维细胞系进行的免疫荧光研究表明，只有一小部分野生型细胞能够被感染，并且在少数被感染的野生型细胞中，病毒复制在早期核阶段就会终止。除肺外，在所有检查的器官中，完整的I型干扰素反应显然可预防甲型流感病毒WSN/33感染。我们的结果表明，I型干扰素在体内和体外确定甲型流感病毒A/WSN/33的致病性和组织限制性方面起着重要作用。
