Human Metapneumovirus Inhibits IFN-β Signaling by Downregulating Jak1 and Tyk2 Cellular Levels

Junping Ren,Antonella Casola,Roberto P Garofalo,Xiaoyong Bao,Renling Xu,Tianshuang Liu,Deepthi Kolli,Yuntao Wu

doi:10.1371/journal.pone.0024496

Junping Ren, Antonella Casola + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0024496

Copy DOI

Journal: PloS one	Publication Date: Sep 19, 2011
Citations: 88	License type: CC BY 4.0

Affiliation: The University of Texas Medical Branch at Galveston

Abstract

Human metapneumovirus (hMPV), a leading cause of respiratory tract infections in infants, inhibits type I interferon (IFN) signaling by an unidentified mechanism. In this study, we showed that infection of airway epithelial cells with hMPV decreased cellular level of Janus tyrosine kinase (Jak1) and tyrosine kinase 2 (Tyk2), due to enhanced proteosomal degradation and reduced gene transcription. In addition, hMPV infection also reduced the surface expression of type I IFN receptor (IFNAR). These inhibitory mechanisms are different from the ones employed by respiratory syncytial virus (RSV), which does not affect Jak1, Tyk2 or IFNAR expression, but degrades downstream signal transducer and activator of transcription proteins 2 (STAT2), although both viruses are pneumoviruses belonging to the Paramyxoviridae family. Our study identifies a novel mechanism by which hMPV inhibits STAT1 and 2 activation, ultimately leading to viral evasion of host IFN responses.

Highlights

Human metapneumovirus is a recently identified RNA virus belonging to the family of Paramyxoviridae, subfamily Pneumovirinae, genus Metapneumovirus [1,2,3] Since its discovery, hMPV has been recognized as a leading cause of lower respiratory infection in infants and children worldwide, second only to respiratory syncytial virus (RSV) [2,4,5,6]
To confirm interferon-stimulated genes (ISGs) transcription by hMPV-induced type I IFN, cells were transfected with a luciferase reporter plasmid containing five copies of the IFN-stimulated response elements (ISRE) site derived from interferon-stimulated gene 54 (ISG54) gene promoter, which binds transcription factors belonging to the signal transducer and activator of transcription protein (STAT) family, followed by hMPV infection
We found that infection of A549 cells with hMPV, at an multiplicity of infection (MOI) of 0.5, caused a significant increase in the luciferase activity, compared to mock-treated cells, indicating that hMPV induces transcription of ISRE-dependent genes. hMPV replication was required for viral-induced ISRE-dependent gene transcription, as UV-inactivated hMPV failed to induce significant luciferase activity (Fig. 1A)

Summary

Introduction

Human metapneumovirus (hMPV) is a recently identified RNA virus belonging to the family of Paramyxoviridae, subfamily Pneumovirinae, genus Metapneumovirus [1,2,3] Since its discovery, hMPV has been recognized as a leading cause of lower respiratory infection in infants and children worldwide, second only to respiratory syncytial virus (RSV) [2,4,5,6]. Respiratory epithelial cells are the primary target of hMPV infection. Type I IFNs (IFN-a and IFN-b) are the key mediators produced by airway epithelial cells infected with paramyxoviruses [9,10,11,12], including hMPV [13]. Tyrosine kinase 2 (Tyk2), a kinase belonging to the Jak family, is constitutively bound to IFNAR1 [14].

Methods

Results

Conclusion