Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury.
Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury.
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DOI：
10.1128/mbio.00271-13
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发表时间：
2013-08-06
期刊：
影响因子：
6.4
通讯作者：
Baric RS
中科院分区：
文献类型：
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作者：
Gralinski LE;Bankhead A 3rd;Jeng S;Menachery VD;Proll S;Belisle SE;Matzke M;Webb-Robertson BJ;Luna ML;Shukla AK;Ferris MT;Bolles M;Chang J;Aicher L;Waters KM;Smith RD;Metz TO;Law GL;Katze MG;McWeeney S;Baric RS
系统生物学在揭示病毒和其他微生物病原体与宿主信号和表达网络相互作用以调节疾病严重程度的新途径方面提供了相当大的希望。在本研究中，我们以严重急性呼吸综合征冠状病毒(SARS-CoV)为模型病原体，开发了一种无偏的建模方法来识别介导急性肺损伤的新的途径和网络连接。我们利用匹配的病毒学、病理学和转录学数据的时间进程，在一个新的方法学框架内，可以检测到关键的高度连接的网络基因之间的途径丰富。这种不偏不倚的方法在SARS冠状病毒感染后差异表达的3500多个基因中，产生了一条途径中的4个基因的高优先级列表。根据这些数据，我们预测尿激酶和其他伤口修复途径将调节小鼠感染SARS冠状病毒后的致死性疾病和亚致死性疾病。我们利用基因定义的基因敲除小鼠、途径激活的蛋白质组学相关性和病理疾病严重程度，验证了尿激酶途径对SARS冠状病毒疾病严重程度的重要性。这些研究的结果表明，在感染高致病性呼吸道病毒(如SARS-CoV)后，宿主凝血和纤溶酶途径之间存在着微妙的平衡，这些途径调节着病理疾病的结果，包括弥漫性肺泡损伤和急性肺损伤。严重急性呼吸综合征冠状病毒(SARS-CoV)出现在2002年和2003年，感染患者发展为非典型肺炎、急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)，导致肺纤维化和死亡。我们利用致死性和亚致死性SARS-CoV感染模型确定了一组与ALI和ARDS相关的差异表达基因。对我们的基因集进行数学优先排序，确定了尿激酶和细胞外基质重塑途径是最丰富的途径。通过感染SERPINE1基因敲除小鼠，我们表明尿激酶途径在肺部病理和SARS-CoV的整体发病机制中都有显著的影响。这些结果表明，有效地使用无偏见的建模技术来识别调节疾病结果的高优先级宿主靶标。在1918年和2009年H1N1流感病毒感染的小鼠中也注意到了类似的转录特征，这表明在病毒诱导的ALI的发展中存在一种常见的、潜在的可治疗机制。
Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and 2003, and infected patients developed an atypical pneumonia, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) leading to pulmonary fibrosis and death. We identified sets of differentially expressed genes that contribute to ALI and ARDS using lethal and sublethal SARS-CoV infection models. Mathematical prioritization of our gene sets identified the urokinase and extracellular matrix remodeling pathways as the most enriched pathways. By infecting Serpine1-knockout mice, we showed that the urokinase pathway had a significant effect on both lung pathology and overall SARS-CoV pathogenesis. These results demonstrate the effective use of unbiased modeling techniques for identification of high-priority host targets that regulate disease outcomes. Similar transcriptional signatures were noted in 1918 and 2009 H1N1 influenza virus-infected mice, suggesting a common, potentially treatable mechanism in development of virus-induced ALI.