title: Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus.
abstract: 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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Walsh
authors.forename: John R
authors.initials: JR
authors.lastname: Teijaro
authors.forename: Peter R
authors.initials: PR
authors.lastname: Wilker
authors.forename: Anna
authors.initials: A
authors.lastname: Jatzek
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Fremgen
authors.forename: Subash C
authors.initials: SC
authors.lastname: Das
authors.forename: Tokiko
authors.initials: T
authors.lastname: Watanabe
authors.forename: Masato
authors.initials: M
authors.lastname: Hatta
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinya
authors.forename: Marulasiddappa
authors.initials: M
authors.lastname: Suresh
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
mesh_terms: D000528:Alternaria / Q000737:chemistry; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D056747:Immunomodulation / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology; D053139:Oseltamivir / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013110:Sphingosine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D053139:Oseltamivir; D013110:Sphingosine