Crozat Karine, Georgel Philippe, Rutschmann Sophie, Mann Navjiwan, Du Xin, Hoebe Kasper, Beutler Bruce
Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
Mamm Genome. 2006 May;17(5):398-406. doi: 10.1007/s00335-005-0164-2.
The mouse cytomegalovirus (MCMV) resistome is the set of host genes with nonredundant functions in resistance to MCMV infection. By screening 3,500 G(3) germline mutant mice ( approximately 1,750 gamete equivalents), we have identified eight transmissible mutations that create MCMV susceptibility in C57BL/6 mice. Among these, a mutation called Domino was noted to cause macrophage susceptibility to vesicular stomatitis virus (VSV) in vitro. This accessory phenotype was not corrected by type I interferon (IFN), which suggested a defect of the type I IFN pathway. Domino corresponds to a point mutation that alters the DNA binding domain of STAT1, leading to a defect of STAT1 activation. Identification of the Domino mutation demonstrates that an in vivo MCMV susceptibility screen is feasible and illustrates how it can provide insight into the resistome. Moreover, some mutations are far more deleterious than Domino in MCMV-infected mice, consistent with the interpretation that certain protein(s) unrelated to IFN production or signaling are more important than IFNs with regard to their net antiviral effects.
小鼠巨细胞病毒（MCMV）抗性组是一组在抵抗MCMV感染方面具有非冗余功能的宿主基因。通过筛选3500只G(3)种系突变小鼠（约1750个配子当量），我们鉴定出了8种可传递的突变，这些突变使C57BL/6小鼠对MCMV易感。其中，一种名为Domino的突变在体外被发现会导致巨噬细胞对水疱性口炎病毒（VSV）易感。这种附加表型不能被I型干扰素（IFN）纠正，这表明I型干扰素途径存在缺陷。Domino对应于一个点突变，该突变改变了STAT1的DNA结合结构域，导致STAT1激活缺陷。Domino突变的鉴定表明体内MCMV易感性筛选是可行的，并说明了它如何能够为抗性组提供深入了解。此外，在感染MCMV的小鼠中，一些突变比Domino更具有害性，这与以下解释一致：某些与IFN产生或信号传导无关的蛋白质在其净抗病毒作用方面比IFN更重要。
