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.

The Mature Virion of Ectromelia Virus, a Pathogenic Poxvirus, Is Capable of Intrahepatic Spread and Can Serve as a Target for Delayed Therapy

“…Rather, we think that passive immunization temporarily reduces virus loads, allowing the development of active immunity. This is supported by our previous reports that passive transfer of Abs or memory T cells protects only immunocompetent hosts from mousepox (34,43) and a report by Lustig et al showing that VIG does not permanently protect SCID mice from VACV challenge (28).…”

“…2g, right). In all cases, the positive-control antiserum to the type I IFN binding protein was protective (34), while naive serum was not. Hence, the data obtained with pAbs confirm that the MV protein EVM072 is a better target for late Ab therapy than the EV proteins EVM135 and EVM155.…”

“…Our work described here demonstrates that as measured by survival, viral loads, and liver damage, neutralizing Abs to the MV protein L1R/EVM072 are more effective than cometinhibiting Abs to the EV proteins A33R/EVM135 and B5R/ EVM155 at controlling an otherwise lethal ECTV infection when given after viral dissemination to susceptible but otherwise immunocompetent mice. We have recently shown that blocking IgG1 MAbs to B18R/EVM166, which encode a secreted, nonstructural type I interferon decoy receptor, also cures mousepox when administered after viral dissemination (34). While MAb VMC-78 to the EV protein A33R/EVM135 promoted survival when given at 5 dpi, it did not significantly decrease virus loads or liver pathology 2 days after treatment.…”

“…Production of recombinant A33R, EVM135, B5R, and EVM155 was as previously described (18,33). Production of polyclonal rabbit antibodies (Abs) was also as previously described (34). MAbs VMC-2, VMC-14, and VMC-78 (all IgG1) have been described previously (33,35) and were either obtained from BEI Resources (Manassas, VA) or produced and purified as described previously (33,35).…”

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

“…The extraction of total RNA from tissue and reverse transcription of RNA were carried out as described previously (36), and the PCR was done as before (37). The following dye combinations were used for detection and data normalization: 6-carboxyfluorescein (FAM) (reporter for IFNs, MX-1, and IL-6) and hexachlorofluorescein (HEX) (reporter for glyceraldehyde-3-phosphate dehydrogenase [GAPDH]).…”