Molecular Pathogenesis of Rabies

狂犬病的分子发病机制

• 批准号: 6847113
• 负责人: Bernhard F Dietzschold
• 金额: $ 27.48万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847113
• 关键词: apoptosis; biological signal transduction; gene expression; gene targeting; laboratory mouse; laser capture microdissection; molecular pathology; neuropathology; proteomics; rabies; rabies virus; recombinant virus; virulence; virus cytopathogenic effect; virus genetics; virus protein; virus replication

DESCRIPTION (provided by applicant): Tissue culture-adapted, mouse brain-adapted and natural street rabies virus (RV) strains such as the silver-haired bat-associated strain (SHBRV) differ greatly in their pathogenicity. Although we have shown that the rabies (RV) glycoprotein (RV G) is a major player in the pathogenesis of rabies, our knowledge of molecular mechanisms involved in the pathogenesis of rabies is still not complete. The cryptic human rabies cases caused by SHBRV typify the gap in our understanding of rabies pathogenesis, which is most likely a multigenic trait involving several RV-encoded proteins and transcriptional elements, as well as host factors. Therefore, we will continue using reverse genetics technology to identify elements of the RV genome that are responsible for the unique ability of this street RV not only to enter the CNS from a peripheral site but also to cause invariably lethal neurological disease. We have shown that RV G induces de novo protein synthesis, along with apoptosis. Based on these findings, we speculate that expression of RV G can cause a dramatic change in cell functions and thereby could play a central role in RV pathogenesis. Consequently, we will investigate the mechanism(s) by which the RV G induces host cell gene expression. Results from these studies will have practical implications for the development of safer and more efficacious live rabies vaccines, and will provide further basic information on rabies virus pathogenicity. This information could lead to the development of novel therapeutic strategies against clinical rabies. This is particularly significant in view of the increasing number of human rabies cases where exposure to RV is not recognized and, therefore, conventional post-exposure prophylaxis is not initiated sufficiently early to be effective.

描述（由申请人提供）：组织培养物适应，小鼠脑适应和天然街头狂犬病病毒（RV）菌株，例如银发蝙蝠相关菌株（SHBRV）的致病性有很大差异。尽管我们已经表明狂犬病（RV）糖蛋白（RV G）是狂犬病发病机理中的主要参与者，但我们对狂犬病发病机理的分子机制的了解仍然不完整。由SHBRV引起的隐秘人类狂犬病病例在我们对狂犬病发病机理的理解中典型的差距，这很可能是一种多基因性状，涉及几种RV编码的蛋白质和转录元素以及宿主因素。因此，我们将继续使用反向遗传学技术来识别RV基因组的元素，这些元素不仅使该街道RV的独特能力不仅从外围部位进入CNS，而且还引起致命的神经系统疾病。我们已经表明，RV G诱导从头蛋白质的合成以及凋亡。基于这些发现，我们推测RV G的表达会导致细胞功能发生巨大变化，从而可以在RV发病机理中起核心作用。因此，我们将研究RV G诱导宿主细胞基因表达的机制。这些研究的结果将对更安全，更有效的活狂犬病疫苗的发展具有实际意义，并将提供有关狂犬病病毒致病性的进一步基本信息。这些信息可能导致针对临床狂犬病的新型治疗策略的发展。鉴于未识别出RV的人类狂犬病病例的数量增加，这一点尤其重要，因此，常规的暴露后预防尚未充分发起足够的早期启动以使其有效。