Abstract
Respiratory syncytial virus (RSV) infection in mouse and human lung is associated with pathogenic inflammation and oxidative injury. RSV impairs antioxidant responses by increasing the degradation of transcription factor NF-E2-related factor 2 (NRF2), which controls the expression of several antioxidant enzymes (AOEs). In addition to its protective effects, type I IFNs have been increasingly recognized as important mediators of host pathogenic responses during acute respiratory viral infections. We used a mouse model of RSV infection to investigate the effect of lack of type I interferon (IFN) receptor on viral-mediated clinical disease, airway inflammation, NRF2 expression, and antioxidant defenses. In the absence of type I IFN signaling, RSV-infected mice showed significantly less body weight loss and airway obstruction, as well as a significant reduction in cytokine and chemokine secretion and airway inflammation. Lack of type I IFN receptor was associated with greatly reduced virus-induced promyelocytic leukemia lung protein expression, which we showed to be necessary for virus-induced NRF2 degradation in a cell model of infection, resulting in restoration of NRF2 levels, AOE expression, and airway antioxidant capacity. Our data support the concept that modulation of type I IFN production and/or signaling could represent an important therapeutic strategy to ameliorate severity of RSV-induced lung disease.
Highlights
Type I interferons (IFNs) are a major component of innate host defense against viral infections
In addition to its protective effects, type I IFNs have been increasingly recognized as important mediators of host pathogenic responses during acute respiratory viral infections, such as those caused by influenza viruses, in the context of both naturally acquired and experimental human infections [3,4,5]
As type I IFN production is associated with both protective and pathogenic responses in models of viral infections, we investigated whether lack of type I IFN signaling would confer protection against Respiratory syncytial virus (RSV) infection
Summary
Type I interferons (IFNs) are a major component of innate host defense against viral infections. Loss of IFN type I signaling can usually be associated with uncontrolled viral replication in human natural infections and in experimental animal models [2]. In addition to its protective effects, type I IFNs have been increasingly recognized as important mediators of host pathogenic responses during acute respiratory viral infections, such as those caused by influenza viruses, in the context of both naturally acquired and experimental human infections [3,4,5]. Some of the pathogenic effects triggered by type I IFNs during viral infections have been described, including enhanced cytokine production and inflammation, epithelial cell damage by apoptosis, or T-cell-mediated cytotoxicity, other IFN-dependent pathways which could be critical determinants of disease severity have yet to be characterized (reviewed in [6,7]).
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