Human metapneumovirus inhibits IFN-alpha signaling through inhibition of STAT1 phosphorylation.

Document Type

Article

Publication Date

6-1-2008

Abstract

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-alpha failed to reduce viral replication. Moreover, in lung epithelial cells, hMPV infection prevented IFN-alpha-mediated transactivation of the interferon-stimulated response element (ISRE) and up-regulation of interferon-stimulated genes (ISGs). Further examination of the IFN-alpha signaling cascade showed that hMPV infection prevented IFN-alpha-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-alpha and the surface expression of the IFN-alpha 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.

Publisher

American Thoracic Society

Publication Title

American journal of respiratory cell and molecular biology

ISSN

1535-4989

Volume

38

Issue

6

First Page

661

Last Page

670

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