Interferon-Dependent Mechanisms of Disease Pathogenesis in Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections (LRTIs) in young children and of hospitalization for any reason in the first year of life. Beside supportive management, specific treatments for severe RSV LRTIs are not yet available and the development of an effective vaccine has been a disappointing task for the past five decades. Although pathogen-specific factors are recognized as important contributing factors, the pathogenesis of RSV bronchiolitis and the cellular/molecular mechanisms that determine its clinical severity remain incompletely understood. A hallmark of RSV is its resistance to the canonical antiviral activity of interferon type I (IFN I) and at the same time its paradoxical disease-enhancing properties which have been suggested in recent studies of human infections or experimental animal models. We have also shown that an important component of RSV-mediated pathogenesis is the production of reactive oxygen species (ROS), which combined with viral-induced degradation of NF-E2-related factor 2 (NRF2), a key transcription factor that controls the inducible expression of protective antioxidant enzyme (AOEs) leads to oxidative injury and lung inflammation. We hypothesize that strategies directed to block IFN I activity and to supplement the airway mucosa with AOEs could serve as new therapeutic approaches for RSV infections. In studies that are described in this PhD thesis we demonstrated by the use of mice genetically deficient in IFN I receptor or by neutralizing anti-IFN I receptor antibodies the mechanistic role of IFN I signaling in the process of RSV-induced NRF2 degradation, AOE inhibition, activation of the inflammasome pathway and ultimately airway inflammation and disease. Furthermore, we showed herein that intranasal administration of the antioxidant enzyme catalase, either prior or following experimental RSV infection resulted in remarkable improvement in inflammation and clinical disease in mice. The protective effect of catalase was associated with reduction in the release of inflammatory cytokines/chemokines and airway obstruction.

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Keywords
Respiratory Syncytial Virus, type I interferon, antioxidant enzymes, catalase, and innate immunity
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