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A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection.

Authors
  • Marsolais, David
  • Hahm, Bumsuk
  • Walsh, Kevin B
  • Edelmann, Kurt H
  • McGavern, Dorian
  • Hatta, Yasuko
  • Kawaoka, Yoshihiro
  • Rosen, Hugh
  • Oldstone, Michael B A
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Feb 03, 2009
Volume
106
Issue
5
Pages
1560–1565
Identifiers
DOI: 10.1073/pnas.0812689106
PMID: 19164548
Source
Medline
License
Unknown

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.

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