Antibody inhibition of a viral type 1 interferon decoy receptor cures a viral disease by restoring interferon signaling in the liver.

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.

• Authors: Ren-Huan Xu, Daniel Rubio, Felicia Roscoe, Tracy E Krouse, Mary Ellen Truckenmiller, Christopher C Norbury, Paul N Hudson, Inger K Damon, Antonio Alcamí, Luis J Sigal
• Journal: PLoS pathogens (PLoS Pathog) Vol. 8 Issue 1 Pg. e1002475 (Jan 2012) ISSN: 1553-7374 [Electronic] United States
• PMID: 22241999 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Viral
• Viral Proteins
• Virulence Factors
• Receptor, Interferon alpha-beta

Topics

• Animals
• Antibodies, Viral (immunology, pharmacology)
• Cell Line
• Cricetinae
• Ectromelia virus (immunology, metabolism, pathogenicity)
• Ectromelia, Infectious (drug therapy, immunology, metabolism)
• Female
• Liver (immunology, metabolism, virology)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Receptor, Interferon alpha-beta (antagonists & inhibitors, immunology, metabolism)
• Spleen (immunology, metabolism, virology)
• Variola virus (immunology, metabolism)
• Viral Proteins (antagonists & inhibitors, immunology, metabolism)
• Virulence Factors (antagonists & inhibitors, immunology, metabolism)
• Virus Attachment (drug effects)