Abstract
Respiratory syncytial virus (RSV) infection of BALB/c mice previously immunized with a recombinant vaccinia virus (vacv) expressing the attachment (G) protein of RSV (vacvG) results in pulmonary eosinophilia, which mimics the response of formalin-inactivated RSV-vaccinated children, as well as increased weight loss, clinical illness, and enhanced pause (Penh). We show that RSV infection of eosinophil-deficient mice previously immunized with vacvG results in the development of increased weight loss, clinical illness, and Penh similar to that in wild-type controls. These measures of RSV vaccine-enhanced disease are dependent upon STAT4. Interestingly, neither IL-12 nor IL-23, the two most common STAT4-activating cytokines, proved necessary for the development of disease. We demonstrate that IFN-gamma, which is produced following STAT4 activation, contributes to clinical illness and increased Penh, but not weight loss. Our results have important implications for future RSV vaccine design, suggesting that enhancing a Th1 response may exacerbate disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Eosinophils / immunology*
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Immunologic Memory
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Interleukin-23 / immunology
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Interleukin-23 / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Mutant Strains
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Pulmonary Eosinophilia / immunology
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Pulmonary Eosinophilia / virology
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Respiratory Syncytial Virus Infections / immunology*
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Respiratory Syncytial Virus Infections / prevention & control*
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Respiratory Syncytial Virus Vaccines / immunology*
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Respiratory Syncytial Viruses / immunology
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STAT4 Transcription Factor / immunology
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STAT4 Transcription Factor / metabolism
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STAT6 Transcription Factor / immunology
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STAT6 Transcription Factor / metabolism
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Th1 Cells / immunology*
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Vaccines, Synthetic / immunology
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Viral Proteins / immunology
Substances
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Interleukin-23
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Respiratory Syncytial Virus Vaccines
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STAT4 Transcription Factor
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STAT6 Transcription Factor
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Stat4 protein, mouse
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Stat6 protein, mouse
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Vaccines, Synthetic
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Viral Proteins
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Interleukin-12
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Interferon-gamma