GENETIC STUDIES OF ROTAVIRUS PATHOGENESIS AND DEVELOPMENT OF ROTAVIRUS VACCINES

轮状病毒发病机制的遗传学研究及轮状病毒疫苗的开发

• 批准号: 6098913
• 负责人: Yasutaka Hoshino
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6098913
• 关键词: Rotavirus; gene expression; gene rearrangement; rotavirus vaccines; swine; vaccine development; virulence; virus antigen; virus cytopathogenic effect; virus genetics; virus infection mechanism; virus protein; virus replication

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 epidemiological importance and its application to the development of a safe and effective vaccine. Using this strategy, we were successful in generating four double gene substitution human x bovine rotavirus reassortants, each of which processed the following: (i) the VP4-encoding gene from human rotavirus Wa (VP4:1A); (ii) the VP7-encoding gene from human rotavirus D (VP7:1), DS-1 (VP7:2), P (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 and two human x rhesus rotavirus single gene substitution 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 either bovine rotavirus UK or rhesus rotavirus MMU18006. Recently, unusual VP7 (G) serotypes causing a high incidence of human infection have been detected in various parts of the world including G5 strains in Brazil, and G9 and G10 strains in India. Because of the possibility in the future that such G serotypes might need to be included in our vaccine candidates and therefore to ?be prepared?, we generated three rhesus x human and three bovine x human rotavirus reassortants, each of which had only one gene from human rotavirus encoding G5, G9, or G10 specificity, and the remaining genes from either rhesus rotavirus MMU18006 or bovine rotavirus UK. Such strains may prove to be important for the development of an optimally effective rotavirus vaccine.

以前，在涉及半同源 新生猪无菌系统与猪轮状病毒强毒 株（SB-1A）和无毒力人轮状病毒株（DS-1），和 他们的reflectants，我们证明：（一）第三（VP 3），第四 (VP4)、第九（VP 7）或第十（NSP 4）猪轮状病毒基因，每个 在轮状病毒的毒力中起重要的独立作用 仔猪中的感染;以及（ii）所有四种猪轮状病毒 毒力相关基因是诱导腹泻所必需的 以及仔猪散发轮状病毒。这些观察结果 提出了一种潜在的新策略，用于减弱野生型 具有重要流行病学意义的人类轮状病毒及其 用于开发安全有效的疫苗。 使用这种策略，我们成功地生成了四个双 基因置换人x牛轮状病毒抑制剂， 其处理以下：（i）来自 人轮状病毒Wa（VP 4：1A）;（ii）来自人轮状病毒Wa的VP 7编码基因; 人轮状病毒D（VP 7：1）、DS-1（VP 7：2）、P（VP 7：3）或ST 3 (VP7：4）;和（iii）其余九个基因，包括 牛的VP 3和NSP 4编码基因 英国轮状病毒。此外，我们成功地生成了两个人类x光片 牛和两个人x恒河猴轮状病毒单基因置换 重配株，每个重配株都具有来自 人轮状病毒Wa（VP 4：1A）或DS-1（VP 4：1B）和 牛轮状病毒UK或恒河猴的剩余基因 轮状病毒MMU 18006。最近，不寻常的VP 7（G）血清型 导致人类感染的高发病率， 包括巴西的G5菌株和G9菌株 和印度的G10菌株。因为将来有可能 这种G血清型可能需要包括在我们的疫苗中 候选人，因此？做好准备？我们生成了三个 恒河猴×人和三种牛×人轮状病毒抑制剂， 每一个都只有一个来自人类轮状病毒的基因编码 G5、G9或G10特异性，其余基因来自 恒河猴轮状病毒MMU 18006或牛轮状病毒UK。此类菌株 可能被证明是重要的发展， 有效的轮状病毒疫苗。