title: Influenza-Induced Priming and Leak of Human Lung Microvascular Endothelium upon Exposure to Staphylococcus aureus.
abstract: A major cause of death after influenza virus infection is lung injury due to a bacterial superinfection, yet the mechanism is unknown. Death has been attributed to virus-induced immunosuppression and bacterial overgrowth, but this hypothesis is based on data from the preantibiotic era and animal models that omit antimicrobial therapy. Because of diagnostic uncertainty, most patients with influenza receive antibiotics, making bacterial overgrowth unlikely. Respiratory failure after superinfection presents as acute respiratory distress syndrome, a disorder characterized by lung microvascular leak and edema. The objective of this study was to determine whether the influenza virus sensitizes the lung endothelium to leak upon exposure to circulating bacterial-derived molecular patterns from Staphylococcus aureus. In vitro as well as in vivo models of influenza followed by S. aureus superinfection were used. Molecular mechanisms were explored using molecular biology, knockout mice, and human autopsy specimens. Influenza virus infection sensitized human lung endothelium to leak when challenged with S. aureus, even at low doses of influenza and even when the pathogens were given days apart. Influenza virus increased endothelial expression of TNFR1 both in vitro and in intact lungs, a finding corroborated by human autopsy specimens of patients with influenza. Leak was recapitulated with protein A, a TNFR1 ligand, and sequential infection caused protein A-dependent loss of IκB, cleavage of caspases 8 and 3, and lung endothelial apoptosis. Mice infected sequentially with influenza virus and S. aureus developed significantly increased lung edema that was protein A and TNFR1 dependent. Influenza virus primes the lung endothelium to leak, predisposing patients to acute respiratory distress syndrome upon exposure to S. aureus.
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Changsen
authors.initials: C
authors.lastname: Wang
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.|2 Institute of Medical Science.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Armstrong
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.|3 Department of Laboratory Medicine and Pathobiology.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Sugiyama
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Arata
authors.initials: A
authors.lastname: Tabuchi
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Krauszman
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.affiliation: 4 Department of Pathology, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Brendan
authors.initials: B
authors.lastname: Mullen
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Advani
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.|5 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.affiliation: 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.|2 Institute of Medical Science.|3 Department of Laboratory Medicine and Pathobiology.|6 Interdepartmental Division of Critical Care and.|5 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Warren L
authors.initials: WL
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000502:physiology; D007251:Influenza, Human / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008168:Lung / Q000098:blood supply; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D013203:Staphylococcal Infections / Q000378:metabolism* / Q000473:pathology; D013205:Staphylococcal Protein A / Q000378:metabolism; D013211:Staphylococcus aureus / Q000502:physiology; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D051192:Receptors, Pattern Recognition; D047888:Receptors, Tumor Necrosis Factor, Type I; D013205:Staphylococcal Protein A
keywords: influenza; pneumonia; pulmonary edema; superinfection; tumor necrosis factor receptor type I