title: A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection.
abstract: 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.
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. marlene.brandes@insel.ch
authors.forename: Marlène
authors.initials: M
authors.lastname: Brandes
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.forename: Stefan
authors.initials: S
authors.lastname: Kuchen
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Germain
mesh_terms: D000818:Animals; D018925:Chemokines / Q000276:immunology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000145:classification / Q000502:physiology*; D007251:Influenza, Human / Q000150:complications / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000473:pathology; D009504:Neutrophils / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000503:physiopathology
chemical_list: D018925:Chemokines