A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection.
A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection.
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DOI：
10.1016/j.cell.2013.06.013
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发表时间：
2013-07-03
期刊：
影响因子：
64.5
通讯作者：
Germain RN
中科院分区：
文献类型：
--
作者：
Brandes M;Klauschen F;Kuchen S;Germain RN
对于急性致死性流感感染，病毒对肺上皮细胞的直接损伤与免疫失调的相对致病作用仍未得到解决。在这里，我们采取自上而下的系统方法来解决这个问题。来自感染肺部的多基因转录特征表明，炎症信号网络的激活升高区分了致死性和亚致死性感染。流式细胞术和基因表达分析涉及从感染的肺分离的细胞亚群显示，中性粒细胞流入主要占预测的转录签名。自动成像分析与这些基因表达和流动数据一起确定了趋化因子驱动的前馈回路，该回路涉及由不良致死病毒有力驱动的促炎性中性粒细胞。与这些数据一致，嗜中性粒细胞驱动的反应的减弱而不是消融增加了存活率，而没有改变病毒传播。这些发现确立了至少在某些形式的流感诱导的致死性中破坏性先天性炎症的首要地位，并为感染相关病理的系统解剖提供了路线图。
For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium vs. dysregulated immunity remain unresolved. Here we take a top-down systems approach to this question. Multigene transcriptional signatures from infected lungs suggested that elevated activation of inflammatory signaling networks distinguished lethal from sublethal infections. Flow cytometry and gene expression analysis involving isolated cell subpopulations from infected lungs showed that neutrophil influx largely accounted for the predictive transcriptional signature. Automated imaging analysis together with these gene expression and flow data identified a chemokine-driven feed-forward circuit involving pro-inflammatory neutrophils potently driven by poorly contained lethal viruses. Consistent with these data, attenuation but not ablation of the neutrophil-driven response increased survival without changing viral spread. These findings establish the primacy of damaging innate inflammation in at least some forms of influenza-induced lethality and provide a roadmap for the systematic dissection of infection-associated pathology.
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影响因子：
64.5
作者：
Kastner DL;Aksentijevich I;Goldbach-Mansky R
通讯作者：
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