Viral soluble decoy receptor as a novel treatment for IFN-I triggered diseases

Abstract

Besides its antiviral action, type I interferon (IFN-I) plays a key role in triggering the inflammatory response and immunopathology in a group of autoinflammatory disorders known as interferonopathies. Current therapies for these diseases focus on blocking IFN-I signaling at different levels, but with incomplete success. Throughout evolution, to counteract the host immune response, poxviruses have developed decoy receptors, soluble proteins secreted from infected cells during infection that bind and block key host cytokines. One of these, the poxvirus IFN-I binding protein (IFN{beta}BP) is a unique soluble receptor with the ability to block many IFN-I subtypes with broad species specificity. In addition, this protein interacts with glycosaminoglycans on the cell surface while binding IFN-I, which enhances its immunomodulatory potential by allowing the retention of this receptor around the site of infection. In this study, we have deepened into how the poxvirus IFN{beta}BP modulates IFN-I to apply this knowledge to the development of new anti-IFN-I therapeutics. With this purpose, a set of IFN{beta}BP-based recombinant proteins were generated and tested for their ability to neutralize IFN-I and bind to the cell surface in vitro, and their immunomodulatory action was tested in the mousepox model of pathogenesis. Finally, the therapeutic potential of some of these selected viral IFN-I inhibitors was validated in two different murine models of autoinflammatory disease, imiquimod-induced psoriasis and pristane-induced lupus.