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

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.