Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-07, Vol.108 (29), p.12018-12023
• Main Authors: Walsh, Kevin B, Teijaro, John R, Wilker, Peter R, Jatzek, Anna, Fremgen, Daniel M, Das, Subash C, Watanabe, Tokiko, Hatta, Masato, Shinya, Kyoko, Suresh, Marulasiddappa, Kawaoka, Yoshihiro, Rosen, Hugh, Oldstone, Michael B.A
• Format: Article
• Language: English
• Subjects: Alternaria - chemistry; Animals; Antiviral agents; Antiviral drugs; Biological Sciences; Bronchoalveolar Lavage Fluid - chemistry; Cell Line; Chemokines; Cytokines; Cytokines - immunology; Cytokines - metabolism; Dogs; Drug therapy; drugs; Enzyme-Linked Immunosorbent Assay; Exo- alpha -sialidase; Flow Cytometry; H1N1 subtype influenza A virus; humans; Immune response; immunologic diseases; Immunomodulation; Immunomodulation - immunology; Immunosuppressive agents; Infections; Inflammation; Influenza; Influenza A virus - immunology; Influenza virus; Injuries; Lungs; Male; Mice; Mice, Inbred C57BL; Mortality; Neutralization Tests; Orthomyxoviridae; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - immunology; Oseltamivir; Oseltamivir - metabolism; Oseltamivir - pharmacology; Oseltamivir - therapeutic use; pandemic; Pandemics; Pathogenesis; Progeny; Replication; sialidase; sphingosine; Sphingosine - metabolism; Sphingosine - pharmacology; Sphingosine - therapeutic use; Swine flu; T lymphocytes; therapeutics; Vehicles; virus replication; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1107024108

Human pandemic H1N1 2009 influenza virus rapidly infected millions worldwide and was associated with significant mortality. Antiviral drugs that inhibit influenza virus replication are the primary therapy used to diminish disease; however, there are two significant limitations to their effective use: (i) antiviral drugs exert selective pressure on the virus, resulting in the generation of more fit viral progeny that are resistant to treatment; and (ii) antiviral drugs do not directly inhibit immune-mediated pulmonary injury that is a significant component of disease. Here we show that dampening the host's immune response against influenza virus using an immunomodulatory drug, AAL-R, provides significant protection from mortality (82%) over that of the neuraminidase inhibitor oseltamivir alone (50%). AAL-R combined with oseltamivir provided maximum protection against a lethal challenge of influenza virus (96%). Mechanistically, AAL-R inhibits cellular and cytokine/chemokine responses to limit immunopathologic damage, while maintaining host control of virus replication. With cytokine storm playing a role in the pathogenesis of a wide assortment of viral, bacterial, and immunologic diseases, a therapeutic approach using sphingosine analogs is of particular interest.