Abstract
Type 1 interferons (T1-IFNs) play a major role in antiviral defense, but when or how they protect during infections that spread through the lympho-hematogenous route is not known. Orthopoxviruses, including those that produce smallpox and mousepox, spread lympho-hematogenously. They also encode a decoy receptor for T1-IFN, the T1-IFN binding protein (T1-IFNbp), which is essential for virulence. We demonstrate that during mousepox, T1-IFNs protect the liver locally rather than systemically, and that the T1-IFNbp attaches to uninfected cells surrounding infected foci in the liver and the spleen to impair their ability to receive T1-IFN signaling, thus facilitating virus spread. Remarkably, this process can be reversed and mousepox cured late in infection by treating with antibodies that block the biological function of the T1-IFNbp. Thus, our findings provide insights on how T1-IFNs function and are evaded during a viral infection in vivo, and unveil a novel mechanism for antibody-mediated antiviral therapy.
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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Antibodies, Viral / immunology
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Antibodies, Viral / pharmacology*
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Cell Line
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Cricetinae
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Ectromelia virus / immunology
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Ectromelia virus / metabolism*
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Ectromelia virus / pathogenicity
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Ectromelia, Infectious / drug therapy
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Ectromelia, Infectious / immunology*
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Ectromelia, Infectious / metabolism
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Female
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Liver / immunology
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Liver / metabolism
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Liver / virology
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Mice
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Mice, Inbred BALB C
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Mice, SCID
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Receptor, Interferon alpha-beta / antagonists & inhibitors*
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Receptor, Interferon alpha-beta / immunology
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Receptor, Interferon alpha-beta / metabolism
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Spleen / immunology
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Spleen / metabolism
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Spleen / virology
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Variola virus / immunology
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Variola virus / metabolism
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Viral Proteins / antagonists & inhibitors*
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Viral Proteins / immunology
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Viral Proteins / metabolism
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Virulence Factors / antagonists & inhibitors*
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Virulence Factors / immunology
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Virulence Factors / metabolism
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Virus Attachment / drug effects
Substances
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Antibodies, Viral
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Viral Proteins
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Virulence Factors
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Receptor, Interferon alpha-beta