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Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease

¹ Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; ² Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; ³ INFANT Foundation, Buenos Aires, Argentina; ⁴ Tohoku University Graduate School of Medicine, Sendai, Japan

Correspondence and requests for reprints should be addressed to Hye-Youn Cho, Ph.D., Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Building 101, MD D-201, 111 TW Alexander Dr., Research Triangle Park, NC 27709. E-mail: cho2{at}niehs.nih.gov

Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of significant lower respiratory illness in infants and young children, but its pathogenesis is not fully understood. The transcription factor Nrf2 protects lungs from oxidative injury and inflammation via antioxidant response element (ARE)-mediated gene induction.

Objectives: The current study was designed to determine the role of Nrf2-mediated cytoprotective mechanisms in murine airway RSV disease.

Methods: Nrf2-deficient (Nrf2^–/–) and wild-type (Nrf2^+/+) mice were intranasally instilled with RSV or vehicle. In a separate study, Nrf2^+/+ and Nrf2^–/– mice were treated orally with sulforaphane (an Nrf2-ARE inducer) or phosphate-buffered saline before RSV infection.

Measurements and Main Results: RSV-induced bronchopulmonary inflammation, epithelial injury, and mucus cell metaplasia as well as nasal epithelial injury were significantly greater in Nrf2^–/– mice than in Nrf2^+/+ mice. Compared with Nrf2^+/+ mice, significantly attenuated viral clearance and IFN-, body weight loss, heightened protein/lipid oxidation, and AP-1/NF-B activity along with suppressed antioxidant induction was found in Nrf2^–/– mice in response to RSV. Sulforaphane pretreatment significantly limited lung RSV replication and virus-induced inflammation in Nrf2^+/+ but not in Nrf2^–/– mice.

Conclusions: The results of this study support an association of oxidant stress with RSV pathogenesis and a key role for the Nrf2-ARE pathway in host defense against RSV.

Key Words: airway • oxidative stress • antioxidant response element • inflammation • sulforaphane

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Respiratory syncytial virus (RSV) remains the leading cause of severe lower airway disease in infants and in susceptible adults. Although extensive clinical and animal studies have been directed to RSV recently, the mechanisms of susceptibility and etiology remain unclear. What This Study Adds to the Field RSV pathogenesis is implicated with oxidative stress, and the Nrf2-directed pathway contributes to host protection against RSV. Suppressed RSV disease phenotypes by an Nrf2 inducer suggest a potential therapeutic strategy for susceptible individuals.

 

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