Inhibition of the Innate Immune Response by the SARS Coronavirus

描述(申请人提供)：严重急性呼吸系统综合症(SARS)是一种潜在的致命疾病，似乎起源于2002年秋季的广东省中国。这种疾病是由一种新的人类冠状病毒(CoV)引起的，这种病毒被称为SARS-CoV。SARS-CoV是一种高致病性疾病，与其他人类冠状病毒相比，死亡率更高。这种增加的发病机制的病毒基础尚未确定。我们已经证明，SARS-CoV能够在感染过程中调节先天免疫反应。这项应用旨在表征两种新发现的病毒蛋白，我们已经证明它们能够改变细胞中的干扰素反应。我已经确定了两种病毒编码的蛋白质，它们能够阻止干扰素的诱导和细胞内的信号传递。我们将利用细胞生物学和生化技术来研究免疫调节蛋白的作用机制。我们将利用我们针对SARS的反向遗传系统，进一步确定SARS蛋白在体内的功能，该系统使我们能够删除或突变相关基因，并在SARS感染的小鼠模型中评估这些突变对病毒发病的影响。利用一种新创造的小鼠适应的SARS病毒，它不同于SARS的野生型分离株，它确实能在小鼠中引起重大的病理和死亡，我们将阐明该病毒的免疫修饰蛋白对疾病病理结果的作用机制。SARS冠状病毒是研究病毒感染对肺部病理影响的模式生物。识别SARS中肺损伤和疾病进展的途径将使人们更好地了解药物，并为抗击肺部疾病的全球负担提供潜在的新靶点。在对全球疾病负担进行排名时，世卫组织将肺部疾病确定为世界上最常见的疾病类型，超过了艾滋病毒/艾滋病、腹泻疾病、疟疾和结核病。识别导致SARS发病和病理的基因和机制可能直接导致对其他肺部疾病更好的治疗选择。

DESCRIPTION (provided by applicant): Severe acute respiratory syndrome (SARS) is a potentially fatal disease that appears to have originated in the Guandong Province of China in the fall of 2002. The disease is caused by a new human coronavirus (CoV), named the SARS-CoV. SARS-CoV produces a highly pathogenic disease with increase mortality compared to other human coronaviruses. The viral basis for this increase pathogenesis has not been identified. We have shown that the SARS-CoV is able to modulate the innate immune response during infection. This application aims to characterize two newly identified viral proteins that we have shown are able to modify the Interferon response in cells. I have identified two virally encoded proteins that are able to block Interferon induction and signaling in cells. We will investigate the mechanism of action of the immune modulating proteins using cell biological and biochemical techniques. We will further characterize the function of the SARS proteins in vivo, using our reverse genetic system for SARS which enables us to delete or mutate the genes in question and evaluate the effects of those mutations on viral pathogenesis in a mouse model of SARS infection. Using a newly created mouse adapted SARS virus, which unlike the wild type isolates of SARS, does cause significant pathology and death in mice, we will elucidate the mechanism that immune modifying proteins of the virus have on the pathological outcome of disease. The SARS Coronavirus is a model organism to investigate the effects of virus infection on lung pathology. Identification of the pathway of lung damage and disease progression in SARS will enable better understanding and potential new targets for drugs to combat the worldwide burden of lung diseases. When ranking the global burden of disease, the WHO identifies lung disease as the most prevalent type of disease in the world, outranking HIV/AIDS, diarrheal disease, Malaria and Tuberculosis. Identification of the genes and mechanisms contributing to SARS pathogenesis and pathology may lead directly to better treatment options for other lung diseases.