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抵抗力是由单个常染色体显性等位基因(FLV)控制的。耐药小鼠对其他类型的病毒敏感，但对迄今测试的所有黄病毒引起的疾病具有抵抗力，包括西尼罗河病毒、登革热病毒、日本脑炎病毒和森林脑炎病毒。耐药小鼠和细胞培养物有效地感染黄病毒，但产生的病毒产量低于敏感小鼠。耐药表型是结构性表达的，不需要干扰素诱导。通过对小鼠的重组研究，将FIV基因座定位到小鼠5号染色体上的一个区域。2‘-5’-寡腺苷合成酶基因Oas1b的一个等位基因被定位克隆策略鉴定为FIV(Perelygin等人，PNAS 99：9322-9327,2002)。在10个品系的小鼠中观察到了基因和表型的相关性。对黄病毒敏感的小鼠品系在该基因的外显子4上发生了从C到T的转换，导致过早终止密码子和表达截断的蛋白质。这项申请提出了一些OAS基因敲除和敲除小鼠品系的产生，这些品系将用于研究以解决以下问题。(1)。Oas1b抗性等位基因是否就是赋予易感小鼠对黄病毒诱导的疾病的抵抗力所需的全部？核糖核酸酶L在耐药表型中起作用吗？其他小鼠Oas1基因是否在宿主防御黄病毒中发挥作用？不同的小鼠Oas1基因在宿主对特定病毒组的防御中是否发挥着独特的作用？小鼠的所有OAS1基因都能被删除吗？本研究获得的转基因小鼠株系不仅对进一步研究Oas1b介导的抗黄病毒诱导的疾病的机制以及研究新的细胞内抗黄病毒途径是必不可少的，而且它们也是未来研究对其他病毒组的先天免疫反应的宝贵资源。

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.