Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
mBio. 2013 Aug 6;4(4):e00271-13. doi: 10.1128/mBio.00271-13.
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.
系统生物学提供了很大的希望，可以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从而介导疾病严重程度的新途径。在这项研究中，我们开发了一种无偏建模方法，以鉴定介导急性肺损伤的新途径和网络连接，使用严重急性呼吸综合征冠状病毒（SARS-CoV）作为模型病原体。我们利用了一种新的方法学框架中的病毒学、病理学和转录组学数据的时间过程，可以在关键的高连接网络基因中检测途径富集。这种无偏方法产生了一条途径中的 4 个高优先级基因列表，这些基因在 SARS-CoV 感染后有超过 3500 个基因的差异表达。有了这些数据，我们预测尿激酶和其他伤口修复途径将调节 SARS-CoV 感染后小鼠的致死性与亚致死性疾病。我们使用遗传定义的敲除小鼠、途径激活的蛋白质组学相关性和病理学疾病严重程度验证了尿激酶途径对 SARS-CoV 疾病严重程度的重要性。这些研究的结果表明，宿主凝血和纤维蛋白溶解途径之间存在微妙的平衡，调节着包括弥漫性肺泡损伤和急性肺损伤在内的病理疾病结果，这是感染高致病性呼吸道病毒（如 SARS-CoV）后出现的。
严重急性呼吸综合征冠状病毒（SARS-CoV）于 2002 年和 2003 年出现，感染患者会出现非典型肺炎、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。我们使用致死性和亚致死性 SARS-CoV 感染模型鉴定了导致 ALI 和 ARDS 的差异表达基因集。我们基因集的数学优先级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 敲除小鼠，我们表明尿激酶途径对肺病理学和 SARS-CoV 发病机制的整体有显著影响。这些结果表明，无偏建模技术可有效用于鉴定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观察到了类似的转录特征，这表明在病毒诱导的 ALI 发展中存在共同的、潜在可治疗的机制。
