Combined blockade of IFN-Type I and TNF alpha receptors provides protection against respiratory syncytial virus (RSV)-induced disease and bronchoconstriction

Abstract

Abstract While the anti-viral/protective role of interferon type I (IFN-I) and tumor necrosis factor (TNF)-α in naturally acquired RSV infections remains controversial, human and animal studies suggest the existence of a cross-regulation between these two innate pathways, which may contribute to disease and airway inflammation characteristics of this infection. In this study, we investigated the role of IFN-I:TNF-α axis in a mouse model of RSV infection, which provides robust experimental evidence of clinical disease, airway bronchoconstriction and viral replication, recapitulating aspects of the human infection. BALB/c mice were treated with antibodies targeting the IFN-I receptor (IFNR) and either TNF receptor (TNFR)1 or TNFR2 prior to RSV infection. Significant improvements to body-weight loss, illness score and bronchoconstriction measured by plethysmography were observed in mice treated with either antibody combination vs untreated mice (RSV/IgG control). Additionally, several cytokines were significantly reduced in both RSV-IFNR-TNFR mice including IL-1α (p=0.02), IL-6 (p=0.0002), IL-9 (p=0.003), IL-17 (p=0.01), IFN-γ (p=0.005), Ccl3 (p=0.01), Ccl4 (p=0.0003) and Ccl5 (p=0.02). While lung viral load in RSV-IFNR-TNFR1 mice remained comparable to the RSV control (p=0.30), RSV-IFNR-TNFR2 mice had a significant increase in viral replication (p=0.001). Interestingly, this increase in viral replication was not appreciated in previous works blocking IFNR or TNFR2 alone in a similar experimental RSV model. This data collectively demonstrates a synergism between IFN-I and TNF-α during RSV infection as well as highlights the importance of selective receptor blockade when considering RSV therapeutic development.