PPG: SARS-CoV-host cell interactions and vaccine development

项目摘要：由一种新型冠状病毒(SARS-CoV)引起的严重急性呼吸综合征(SARS-CoV)在2002-2003年间导致了相当大的发病率和死亡率。由于SARS没有复发，了解发病机制和开发有效疫苗的研究工作在很大程度上已经停止。然而，在中国的蝙蝠和其他动物种群中已经发现了类似SARS冠状病毒的病毒，这使得SARS有可能复发。因此，我们认为需要继续努力了解发病机制，并开发疫苗和抗病毒疗法。在这次PPG中，几位在冠状病毒感染的发病机制、分子生物学和免疫学方面具有丰富经验的研究人员将合作，以更好地了解SARS-CoV与宿主呼吸道的相互作用，并开发预防和治疗SARS-CoV感染的新方法。这些目标将在以下项目中进行调查。项目1将调查感染小鼠适应的SARS冠状病毒的年轻BALB/c和老年BALB/c和C57BL/6小鼠以及人类细胞受体(血管紧张素转换酶2，hACE2)转基因的SARS冠状病毒感染小鼠的严重疾病。项目2将侧重于ACE2信号在发病机制中的作用。该项目还将通过比较感染SARS-CoV和HCoV-NL63的细胞和小鼠来研究ACE2的作用。HCoV-NL63是一种普通感冒病毒，也使用ACE2进入细胞，但不会导致严重疾病。项目3将研究两种新的抗病毒疗法(恒河猴防御素和格里菲辛)的作用机制，并将研究ACE2脱落在发病机制中的作用。项目4将开发和评估SARS-CoV减毒活疫苗，其基础是观察到在小包膜蛋白中删除的病毒是活的、免疫原性的和安全的。所有项目都将使用病毒学/动物模型核心，该核心将设计和繁殖重组SARSCoV，并分析受感染的小鼠。将核心用于这些目的将确保可重复性，并确保最有效地利用我们的资源。这些项目都是相互关联的，将提供有关SARS-CoV发病机制的新信息，并将利用项目主任的独特技能和专业知识。

Project Summary: The Severe Acute Respiratory Syndrome, caused by a novel coronavlrus (SARS-CoV), resulted in substantial morbidity and mortality in 2002-2003. With the lack of recurrence of SARS, research efforts to understand pathogenesis and develop an effective vaccine have largely halted. However, coronaviruses similar to SARS-CoV have been identified in bats and other animal populations in China, making recurrence of SARS a possibility. Thus, we believe that efforts need to continue to understand pathogenesis and to develop vaccines and anti-viral therapies. In this PPG, several investigators with extensive experience in the pathogenesis, molecular biology and immunology of coronavirus infections will work together to better understand the interaction of SARS-CoV with the host respiratory tract and to develop novel approaches to preventing and treating SARS-CoV infections. These objectives will be investigated in the following projects. Project 1 will investigate severe disease in young BALB/c and aged BALB/c and C57BL/6 mice infected with mouse-adapted SARS-CoV and in SARS-CoV-infected mice that are transgenic for the human cellular receptor (angiotensin converting enzyme 2, hACE2). Project 2 will focus on the role of ACE2 signaling in pathogenesis. This project will also investigate the role of ACE2 by comparing cells and mice infected with SARS-CoV and HCoV-NL63, a common cold virus that also uses ACE2 to enter cells but does not cause severe disease. Project 3 will investigate the mechanism of action of two novel anti-virus therapies (rhesus theta defensin and griffithsin) and will investigate the role of ACE2 shedding in pathogenesis. Project 4 will develop and evaluate live attenuated SARS-CoV vaccines, based on the observation that virus deleted in the small envelope protein is viable, immunogenic and safe. All of the projects will use the Virology/Animal Models Core, which will engineer and propagate recombinant SARSCoV and will also analyze infected mice. Using the Core for these purposes will ensure reproducibility and ensure most effective use of our resources. These projects are all interrelated, will provide new information about SAR-CoV pathogenesis and will take advantage of the unique skills and expertise of the project directors.