The Tie2-agonist Vasculotide rescues mice from influenza virus infection

• Published in: Scientific reports Vol. 5; no. 1; p. 11030
• Main Authors: Sugiyama, Michael G., Armstrong, Susan M., Wang, Changsen, Hwang, David, Leong-Poi, Howard, Advani, Andrew, Advani, Suzanne, Zhang, Haibo, Szaszi, Katalin, Tabuchi, Arata, Kuebler, Wolfgang M., Van Slyke, Paul, Dumont, Dan J., Lee, Warren L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2015; Nature Publishing Group
• Subjects: 13; 13/106; 14; 14/19; 631/326/596/1578; 64/110; 692/420/254; Animal models; Animals; Antiviral agents; Apoptosis; Bronchoalveolar Lavage Fluid - cytology; Cells, Cultured; Disease Models, Animal; Disease resistance; Edema; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Hypoxemia; Infections; Influenza; Influenza A Virus, H1N1 Subtype - physiology; Influenza A Virus, H3N2 Subtype - physiology; Lungs; Mice; Mice, Inbred C57BL; Microvasculature; multidisciplinary; Neutrophils - cytology; Neutrophils - immunology; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - mortality; Orthomyxoviridae Infections - pathology; Pandemics; Peptides - pharmacology; Peptides - therapeutic use; Receptor, TIE-2 - agonists; Receptor, TIE-2 - metabolism; Rodents; Science; Strains (organisms); Survival Rate; Virus Replication - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep11030

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.