GENETIC STUDIES OF ROTAVIRUS PATHOGENESIS

此前，在涉及灵知生菌半同源系统的研究中 新生猪和一株强毒猪轮状病毒(SB-1A)和一只 人轮状病毒弱毒株(DS-1)及其重组体 证明：(1)第三(VP3)、第四(VP4)、第九(VP7)或 猪轮状病毒第十(Nsp4)基因各自发挥重要的独立作用 在轮状病毒感染仔猪的毒力中所起的作用；及 猪轮状病毒毒力相关基因中的四个是 仔猪引起腹泻和轮状病毒的脱落。这些 观察结果提示了一种潜在的新的衰减策略 具有重要流行病学意义的野生型人轮状病毒及其研究进展 应用于开发安全有效的疫苗。 使用这个策略，我们成功地产生了四个人×牛 轮状病毒重组体，每个重组体具有：(I)VP-4编码基因 来自人类轮状病毒Wa(VP4：1A)；(Ii)来自人类的VP7编码基因 轮状病毒D(VP7：1)、DS-1(VP7：3)或ST3(VP7：4)；及 其余9个基因包括VP3编码基因和NSP4编码基因 来自牛轮状病毒英国的基因。此外，我们还成功地生成了 两个人x牛轮状病毒重组体，每一个都有 人轮状病毒Wa(VP4：1A)或DS-1(VP4：1B)的VP4编码基因和 来自牛轮状病毒英国的剩余基因。此外，我们还拥有 产生了另外两个人x恒河猴轮状病毒重组体，每个 它具有来自人类轮状病毒WA(VP4：1A)或DS-1的VP4编码基因 (VP4：1B)，人轮状病毒DS-1的VP7编码基因(VP7：2)和 其余9个基因来自恒河猴轮状病毒MMU18006。最近，我们 产生了一个额外的人x恒河猴轮状病毒重组体， 有10个来自恒河猴轮状病毒的基因和来自人类轮状病毒的VP7基因 P(VP7：3)。这些菌株可能会被证明对发展 一种最有效的轮状病毒疫苗。

Previously, in studies involving a semi-homologous system of gnotobiotic newborn pigs and a virulent porcine rotavirus strain (SB-1A) and an avirulent human rotavirus strain (DS-1) and their reassortants, we demonstrated that: (i) the third (VP3), fourth (VP4), ninth (VP7), or tenth (NSP4) porcine rotavirus gene each play an important independent role in the virulence of rotavirus infection in piglets; and (ii) all four of the porcine rotavirus virulence-associated genes are required for the induction of diarrhea and the shedding of rotavirus by piglets. These observations suggested a potential new strategy for attenuation of wild-type human rotaviruses of major epidemiologic importance and its application to the development of a safe and effective vaccine. Using this strategy, we were successful in generating four human x bovine rotavirus reassortants, each of which has: (i) the VP-4 encoding gene from human rotavirus Wa (VP4:1A); (ii) VP7-encoding gene from human rotavirus D (VP7:1), DS-1 (VP7:3), or ST3 (VP7:4); and (iii) the remaining nine genes including the VP3-encoding gene and NSP4-encoding gene from bovine rotavirus UK. In addition, we successfully generated two human x bovine rotavirus reassortants, each of which had the VP4-encoding gene from human rotavirus Wa (VP4:1A) or DS-1 (VP4:1B) and the remaining genes from bovine rotavirus UK. Furthermore, we have generated two additional human x rhesus rotavirus reassortants, each of which has the VP4-encoding gene from human rotavirus Wa (VP4:1A) or DS-1 (VP4:1B), the VP7-encoding gene from human rotavirus DS-1 (VP7:2) and the remaining nine genes from rhesus rotavirus, MMU18006. More recently, we have generated an additional human x rhesus rotavirus reassortant which has ten genes from rhesus rotavirus and the VP7 gene from human rotavirus P (VP7:3). Such strains may prove to be useful for the development of an optimally effective rotavirus vaccine.