Oas-1 gene transgenic mice for WNV research.

描述（由申请人提供）： 小鼠对黄病毒发病率和死亡率的抗性由单个常染色体显性等位基因（Flv）控制。耐药小鼠对其他类型的病毒敏感，但对迄今为止测试的所有黄病毒诱导的疾病具有抗性，包括西尼罗河病毒、登革热病毒、日本脑炎病毒和蜱传脑炎病毒。抗性小鼠和细胞培养物被黄病毒有效感染，但产生的病毒产量低于易感小鼠。耐药表型是组成型表达的，不需要IFN诱导。通过小鼠重组研究将FIv基因座定位于小鼠5号染色体上的一个区域。使用定位克隆策略将2 ′-5 ′-寡腺苷酸合成酶基因Oas 1b的等位基因鉴定为FIv（Perelygin等，PNAS 99：9322-9327，2002）。在10个品系的小鼠中观察到基因型和表型之间的相关性。对黄病毒易感的小鼠品系在基因的外显子4中具有C到T的转变，导致提前终止密码子和截短蛋白的表达。本申请提出了许多Oas基因敲入和敲除小鼠品系的产生，其将用于研究以解决以下问题。（一）. Oas 1b耐药等位基因是否是易感小鼠对黄病毒诱导疾病产生耐药性的全部条件？（二）、RNase L在抗性表型中起作用吗？（三）、其他小鼠Oas 1基因在宿主防御黄病毒中发挥作用吗？（四）、不同的小鼠Oas 1基因在宿主防御特定病毒群中发挥独特作用吗？（五）、所有的小鼠Oas 1基因都可以被删除吗？本研究中产生的转基因小鼠品系不仅对于Oas 1b介导的对黄病毒诱导的疾病的抗性机制的进一步研究以及新型细胞内抗黄病毒途径的研究至关重要，而且它们也代表了对其他病毒组的先天免疫应答的未来研究的宝贵资源。

DESCRIPTION (provided by applicant): Resistance to flavivirus morbidity and mortality in mice is controlled by a single autosomal-dominant allele (Flv). Resistant mice are susceptible to other types of viruses but are resistant to disease induced by all flaviviruses tested to date, including West Nile, Dengue, Japanese encephalitis and tickborne encephalitis viruses. Resistant mice and cell cultures are efficiently infected by flaviviruses but produce lower yields of virus than susceptible mice. The resistant phenotype is constitutively expressed and does not require IFN induction. The FIv locus was mapped to a region on mouse chromosome 5 by recombination studies in mice. An allele of the 2'-5'-oligoadenylate synthetase gene, Oas1b, was identified as FIv using a positional cloning strategy (Perelygin et al., PNAS 99: 9322-9327, 2002). A correlation between genotype and phenotype was observed in 10 mouse strains. Mouse strains that are susceptible to flaviviruses have a C-to-T transition in exon 4 of the gene resulting in a premature stop codon and the expression of a truncated protein. This application proposes the generation of a number of Oas gene knock-in and knockout mouse strains that will be used in studies to address the following questions. (1). Is the Oas1b resistant allele all that is required to confer resistance to flavivirus-induced disease in a susceptible mouse? (2). Does RNase L play a role in the resistance phenotype? (3). Do other mouse Oas1 genes play a role in host defense against flaviviruses? (4). Do different mouse Oas1 genes play unique roles in host defense to specific groups of viruses? (5). Can all of the mouse Oas1 genes be deleted? The strains of transgenic mice generated in this study are not only essential for further studies of the mechanism of Oas1b-mediated resistance to flavivirus-induced disease as well as the study of novel intracellular anti-flaviviral pathways, but they also represent a valuable resource for future studies on innate immune responses to other groups of viruses.