A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection

Brandes, Marlène; Klauschen, Frederick; Kuchen, Stefan; Germain, Ronald N. (2013). A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection. Cell, 154(1), pp. 197-212. Cell Press 10.1016/j.cell.2013.06.013

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology
04 Faculty of Medicine > Department of General Internal Medicine (DAIM) > Clinic of General Internal Medicine

UniBE Contributor:

Brandes Kuchen, Marlène and Kuchen, Stefan

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0092-8674

Publisher:

Cell Press

Language:

English

Submitter:

Stefan Kuchen

Date Deposited:

23 Apr 2014 09:31

Last Modified:

06 Nov 2015 09:19

Publisher DOI:

10.1016/j.cell.2013.06.013

PubMed ID:

23827683

BORIS DOI:

10.7892/boris.43234

URI:

https://boris.unibe.ch/id/eprint/43234

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