title: A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection.
abstract: Pulmonary tissue damage resulting from influenza virus infection is caused by both the cytolytic activity of the virus and the host immune response. Immune-mediated injury results from T cell-mediated destruction of virus-infected cells and by release of cytokines and chemokines that attract polymorphonuclear leukocytes (PML) and macrophages to the infected site. The cytokines/chemokines potentiate dendritic cell (DC) activation and T cell expansion, which further enhances local damage. Here we report that immune modulation by local administration to the respiratory tract of sphingosine analog AAL-R significantly dampens the release of cytokines and chemokines while maintaining protective neutralizing antibody and cytotoxic T cell responses. As a result there was a marked reduction of infiltrating PML and macrophages into the lung and resultant pulmonary tissue injury. DC maturation was suppressed, which limited proliferation of specific antiviral T cells in the lung and draining lymph nodes. Further, AAL-R was effective in controlling CD8(+) T cell accumulation in the lungs even when given 4 days after initiation of influenza virus infection. These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus.
authors.affiliation: Department of Chemical Physiology and Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Marsolais
authors.forename: Bumsuk
authors.initials: B
authors.lastname: Hahm
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Walsh
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Edelmann
authors.forename: Dorian
authors.initials: D
authors.lastname: McGavern
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hatta
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: D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis*; D004279:DNA, Viral; D004195:Disease Models, Animal; D006801:Humans; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D013110:Sphingosine / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D004279:DNA, Viral; D013110:Sphingosine