IPS-1 Signaling Has a Nonredundant Role in Mediating Antiviral Responses and the Clearance of Respiratory Syncytial Virus

Abstract

The cytosolic RNA helicases melanoma differentiation–associated gene 5 and retinoic acid–inducible gene-I and their adaptor IFN-β promoter stimulator (IPS-1) have been implicated in the recognition of viral RNA and the production of type I IFN. Complementing the endosomal TLR, melanoma differentiation–associated gene 5, and retinoic acid–inducible gene-I provides alternative mechanisms for viral detection in cells with reduced phagocytosis or autophagy. The infection route of respiratory syncytial virus (RSV)—via fusion of virus particles with the cell membrane—points to IPS-1 signaling as the pathway of choice for downstream antiviral responses. In the current study, viral clearance and inflammation resolution were indeed strongly affected by the absence of an initial IPS-1–mediated IFN-β response. Despite the blunted inflammatory response in IPS-1–deficient alveolar epithelial cells, pulmonary macrophages, and CD11b+ dendritic cells (DC), the lungs of RSV-infected IPS-1–knockout mice showed augmented recruitment of inflammatory neutrophils, monocytes, and DC. Interestingly, pulmonary CD103+ DC could functionally compensate for IPS-1 deficiency with the upregulation of certain inflammatory cytokines and chemokines, possibly via TLR3 and TLR7 signaling. The increased inflammation and reduced viral clearance in IPS-1–knockout mice was accompanied by increased T cell activation and IFN-γ production. Experiments with bone marrow chimeras indicated that RSV-induced lung pathology was most severe when IPS-1 expression was lacking in both immune and nonimmune cell populations. Similarly, viral clearance was rescued upon restored IPS-1 signaling in either the nonimmune or the immune compartment. These data support a nonredundant function for IPS-1 in controlling RSV-induced inflammation and viral replication.