Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4239-44. doi: 10.1073/pnas.1114981109. Epub 2012 Feb 27.
Type I and type II interferons (IFNs) are cytokines that establish the cellular antiviral state through the induction of IFN-stimulated genes (ISGs). We sought to understand the basis of the antiviral activity induced by type I and II IFNs in relation to the functions of their ISGs. Based on gene expression studies, we systematically identified antiviral ISGs by performing blinded, functional screens on 288 type I and type II ISGs. We assessed and validated the antiviral activity of these ISGs against an RNA virus, vesicular stomatitis virus (VSV), and a DNA virus, murine gammaherpes virus (MHV-68). Overall, we identified 34 ISGs that elicited an antiviral effect on the replication of either one or both viruses. Fourteen ISGs have uncharacterized antiviral functions. We further defined ISGs that affect critical life-cycle processes in expression of VSV protein and MHV-68 immediate-early genes. Two previously undescribed antiviral ISGs, TAP1 and BMP2, were further validated. TAP1-deficient fibroblasts were more susceptible to VSV infection but less so to MHV-68 infection. On the other hand, exogenous BMP2 inhibits MHV-68 lytic growth but did not affect VSV growth. These results delineate common and distinct sets of type I and type II IFN-induced genes as well as identify unique ISGs that have either broad or specific antiviral effects on these viruses.
I 型和 II 型干扰素（IFNs）是通过诱导干扰素刺激基因（ISGs）来建立细胞抗病毒状态的细胞因子。我们试图了解 I 型和 II 型 IFNs 诱导的抗病毒活性的基础，与它们的 ISGs 的功能有关。基于基因表达研究，我们通过对 288 种 I 型和 II 型 ISGs 进行盲法、功能筛选，系统地鉴定了抗病毒 ISGs。我们评估并验证了这些 ISGs 对 RNA 病毒水疱性口炎病毒（VSV）和 DNA 病毒鼠γ疱疹病毒（MHV-68）的抗病毒活性。总的来说，我们鉴定了 34 种 ISGs，它们对一种或两种病毒的复制都具有抗病毒作用。14 种 ISGs 具有未被描述的抗病毒功能。我们进一步定义了影响 VSV 蛋白表达和 MHV-68 早期基因表达的关键生命周期过程的 ISGs。两个以前未被描述的抗病毒 ISGs，TAP1 和 BMP2，进一步得到了验证。TAP1 缺陷型成纤维细胞对 VSV 感染更敏感，但对 MHV-68 感染则不那么敏感。另一方面，外源性 BMP2 抑制 MHV-68 裂解生长，但不影响 VSV 生长。这些结果描绘了 I 型和 II 型 IFN 诱导的基因的常见和独特集合，并鉴定了具有这些病毒的广谱或特异性抗病毒作用的独特 ISGs。
