牛病毒性腹泻病毒（BVDV）分为致细胞病变型（CP）和非致细胞病变型（NCP）两种生物型，其感染宿主后产生不同的天然免疫反应。干扰素刺激基因15（ISG15）编码重要的抗病毒和免疫调节蛋白。我们前期研究发现，不同生物型BVDV感染MDBK细胞后ISG15表达有显著差异，我们推测，ISG15是调控不同生物型BVDV诱导天然免疫差异的重要分子。为此，本项目拟以ISG15分子蛋白为研究对象，利用CRISPR-Cas9技术、RNAscope、免疫共沉淀等技术，比较CP型和NCP型BVDV感染宿主后ISG15的表达差异及其对病毒复制和免疫功能的影响，并且从体内和体外两方面研究ISG15调控两种生物型BVDV诱导天然免疫差异的分子机制。本项目将明确ISG15在调控不同生物型BVDV诱导天然免疫差异的功能，为研究BVDV诱导先天性免疫应答差异机制和免疫逃逸机制研究提供新的科学资料。

Bovine viral diarrhea virus (BVDV) is divided into cytopathic type (CP) and non-cytopathic type (NCP), which inducing different innate immune responses after infecting the host. Interferon stimulating gene 15 (ISG15) protein is an important antiviral and immunomodulatory protein. Our previous study found that ISG15 expression was significantly different in MDBK cells infected with different biotypes of BVDV, and we hypothesize that ISG15 was an important molecule in regulating innate immune response between the two biotypes of BVDV. Therefore, in this proposal，we will compare the difference of ISG15 between the two biotype BVDV, and then explore the mechanism in the difference of innate immune response by using the CRISPR-Cas9 technology, RNAscope, immune co-precipitation technique. This project will clarify the function of ISG15 in regulating differences in natural immunity induced by the different biotype BVDV. It will provide new scientific data for the study of the mechanism of different biotypes BVDV inducing the innate immune response and immune escape.