A Systems Analysis Identifies a Feedforward Inflammatory Circuit Leading to Lethal Influenza Infection

被引:297
作者
Brandes, Marlene [1 ]
Klauschen, Frederick [3 ]
Kuchen, Stefan [2 ]
Germain, Ronald N. [1 ]
机构
[1] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA
[2] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA
[3] Univ Med Berlin, Inst Pathol, D-10117 Berlin, Germany
关键词
KAPPA-B-ALPHA; IMMUNE-RESPONSE; DENDRITIC CELLS; PROTECTS MICE; HOST IMMUNE; VIRUS; NEUTROPHILS; RECEPTOR; MACROPHAGES; EXPRESSION;
D O I
10.1016/j.cell.2013.06.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium versus 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 feedforward circuit involving proinflammatory 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.
引用
收藏
页码:197 / 212
页数:16
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