title: The Tie2-agonist Vasculotide rescues mice from influenza virus infection.
abstract: Seasonal influenza virus infections cause hundreds of thousands of deaths annually while viral mutation raises the threat of a novel pandemic strain. Antiviral drugs exhibit limited efficacy unless administered early and may induce viral resistance. Thus, targeting the host response directly has been proposed as a novel therapeutic strategy with the added potential benefit of not eliciting viral resistance. Severe influenza virus infections are complicated by respiratory failure due to the development of lung microvascular leak and acute lung injury. We hypothesized that enhancing lung endothelial barrier integrity could improve the outcome. Here we demonstrate that the Tie2-agonist tetrameric peptide Vasculotide improves survival in murine models of severe influenza, even if administered as late as 72 hours after infection; the benefit was observed using three strains of the virus and two strains of mice. The effect required Tie2, was independent of viral replication and did not impair lung neutrophil recruitment. Administration of the drug decreased lung edema, arterial hypoxemia and lung endothelial apoptosis; importantly, Vasculotide is inexpensive to produce, is chemically stable and is unrelated to any Tie2 ligands. Thus, Vasculotide may represent a novel and practical therapy for severe infections with influenza.
authors.affiliation: 1] Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON [2] Department of Laboratory Medicine and Pathobiology, University of Toronto.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Sugiyama
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Armstrong
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Changsen
authors.initials: C
authors.lastname: Wang
authors.affiliation: 1] Department of Laboratory Medicine and Pathobiology, University of Toronto [2] Department of Pathology, Toronto General Hospital, University Health Network, Toronto, ON.
authors.forename: David
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Advani
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Katalin
authors.initials: K
authors.lastname: Szaszi
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Arata
authors.initials: A
authors.lastname: Tabuchi
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON.
authors.forename: Paul
authors.initials: P
authors.lastname: Van Slyke
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON.
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Dumont
authors.affiliation: 1] Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON [2] Department of Laboratory Medicine and Pathobiology, University of Toronto [3] Interdepartmental Division of Critical Care and Department of Medicine, University of Toronto.
authors.forename: Warren L
authors.initials: WL
authors.lastname: Lee
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D042787:Receptor, TIE-2 / Q000819:agonists* / Q000378:metabolism; D015996:Survival Rate; D014779:Virus Replication / Q000187:drug effects
chemical_list: D010455:Peptides; D042787:Receptor, TIE-2; C079086:Tek protein, mouse