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Human Metapneumovirus Inhibits IFN- Signaling through Inhibition of STAT1 Phosphorylation

¹ Infectious Diseases Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico

Correspondence and requests for reprints should be addressed to Kevin S. Harrod, MD, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108. E-mail: kharrod{at}lrri.org

The recently discovered human metapneumovirus (hMPV) is a major cause of lower and upper respiratory tract infections worldwide. Acute viral infection initiates the interferon response that is critical in mediating viral clearance, viral host defense, and development of adaptive immunity. Mouse models of infection suggest that hMPV can cause persistent lung infections, yet the mechanisms of evading host viral clearance are unknown. Here we report that hMPV can subvert host type I interferon signaling by a mechanism distinct from other paramyxoviruses. Two lung epithelial cell lines and primary normal human bronchial epithelial cells (NHBE) were permissive for hMPV, consistent with its tropism for the respiratory tract. Treatment of hMPV-infected cells with exogenous IFN- failed to reduce viral replication. Moreover, in lung epithelial cells, hMPV infection prevented IFN-–mediated transactivation of the interferon-stimulated response element (ISRE) and up-regulation of interferon-stimulated genes (ISGs). Further examination of the IFN- signaling cascade showed that hMPV infection prevented IFN-–induced phosphorylation and nuclear translocation of STAT1. The inhibitory effects of hMPV on STAT1 phosphorylation and translocation were abolished by ultraviolet inactivation. Regulation of STAT1 by hMPV was specific, as phosphorylation of STAT2, Tyk2, and Jak1 by IFN- and the surface expression of the IFN- receptor were unaltered by hMPV infection. These findings demonstrate that hMPV can inhibit the type I interferon response through regulation of STAT1 phosphorylation, and provide important insight into the viral pathogenesis of hMPV infection in the respiratory tract.

Key Words: human metapneumovirus • interferon- • type I interferon • innate immune response • STAT

CLINICAL RELEVANCE Our research with human metapneumovirus (hMPV) provides new insight into the viral mechanisms hMPV uses to inhibit the innate immune response. This will assist in the development of preventive vaccines and/or treatments of hMPV.