tetano
Editor, Senior Moderator
Cell, Volume 154, Issue 1, 197-212, 3 July 2013
Copyright ? 2013 Elsevier Inc. All rights reserved.
10.1016/j.cell.2013.06.013
Authors
Marl?ne Brandessend email, Frederick Klauschen, Stefan Kuchen, Ronald N. Germainsend emailSee Affiliations
Highlights
Early neutrophil infiltration largely accounts for fatal influenza gene signatures
Self-reflexive chemokine feedforward circuits underlie dysregulated inflammation
Fatal interstitial neutrophil activation correlates with unconstrained PAMP encounters
Neutrophil reduction prevents death from self-amplifying damaging inflammation
Summary
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.
http://www.cell.com/abstract/S0092-8674(13)00715-0
Copyright ? 2013 Elsevier Inc. All rights reserved.
10.1016/j.cell.2013.06.013
Authors
Marl?ne Brandessend email, Frederick Klauschen, Stefan Kuchen, Ronald N. Germainsend emailSee Affiliations
Highlights
Early neutrophil infiltration largely accounts for fatal influenza gene signatures
Self-reflexive chemokine feedforward circuits underlie dysregulated inflammation
Fatal interstitial neutrophil activation correlates with unconstrained PAMP encounters
Neutrophil reduction prevents death from self-amplifying damaging inflammation
Summary
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.
http://www.cell.com/abstract/S0092-8674(13)00715-0