Mumps virus Enders strain is sensitive to interferon (IFN) despite encoding a functional IFN antagonist

D F Young,R E Randall,W P Duprex,B K Rima,J Andrejeva,M C Galiano,K Lemon,Y.-H Chen

doi:10.1099/vir.0.013722-0

D F Young, R E Randall + Show 6 more

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https://doi.org/10.1099/vir.0.013722-0

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Abstract

Although the Enders strain of mumps virus (MuV) encodes a functional V protein that acts as an interferon (IFN) antagonist, in multi-cycle growth assays MuV Enders grew poorly in naïve (‘IFN-competent’ Hep2) cells but grew to high titres in ‘IFN-compromised’ Hep2 cells. Even so, the growth rate of MuV Enders was significantly slower in ‘IFN-compromised’ Hep2 cells when compared with its replication rate in Vero cells and with the replication rate of parainfluenza virus type 5 (a closely related paramyxovirus) in both naïve and ‘IFN-compromised’ Hep2 cells. This suggests that a consequence of slower growth is that the IFN system of naïve Hep2 cells can respond quickly enough to control the growth of MuV Enders. This is supported by the finding that rapidly growing variants of MuV Enders that were selected on ‘IFN-compromised’ Hep2 cells (i.e. in the absence of any selection pressure exerted by the IFN response) also grew to high titres on naïve Hep2 cells. Sequencing of the complete genome of one of these variants identified a single point mutation that resulted in a substitution of a conserved asparagine by histidine at position 498 of the haemagglutinin–neuraminidase protein, although this mutation was not present in all rapidly growing variants. These results support the concept that there is a race between the ability of a cell to detect and respond to virus infection and the ability of a virus to block the IFN response. Importantly, this emphasizes that factors other than viral IFN antagonists influence the sensitivity of viruses to IFN.

Highlights

Cells respond to virus infection by secreting alpha and beta interferons (IFN-a/b), which act in both autocrine and paracrine fashions to upregulate the expression of hundreds of cellular genes, the products of many having antiviral functions
mumps virus (MuV) Enders grew to high titres in Hep2 cells engineered to be either unresponsive to IFN (Hep2/parainfluenza virus type 5 (PIV5)-V cells; Young et al, 2003) or unproductive for IFN (Hep2/BVDV-Npro; Hilton et al, 2006; Carlos et al, 2007), illustrating that MuV is sensitive to the IFN response of Hep2 cells (Fig. 1)
STAT1 was clearly degraded by MuV Enders in untreated cells by 8 h p.i. and the high levels of STAT1 in IFNpretreated cells were significantly reduced by 24 h p.i. (Fig. 2a), consistent with previously published work that has shown that the V protein of MuV targets STAT1 for proteasome-mediated degradation (Ulane et al, 2003)

Summary

Introduction

Cells respond to virus infection by secreting alpha and beta interferons (IFN-a/b), which act in both autocrine and paracrine fashions to upregulate the expression of hundreds of cellular genes, the products of many having antiviral functions. RIG-I and mda-5 are two intracellular detectors of viral PAMPs which recognize RNA structures not normally present in cells, such as double-stranded RNA (dsRNA) and/or 59-triphosphorylated, uncapped singlestranded RNA (ssRNA) (Andrejeva et al, 2004; Yoneyama et al, 2004; Hornung et al, 2006; Pichlmair et al, 2006; Kato et al, 2008). When activated by their appropriate ligands, RIG-I and mda-5 initiate a signalling cascade that leads to the synthesis of IFN-a/b. Secreted IFNa/b binds to the IFN-a/b receptor and activates JAK1 and Tyk, two kinases associated with the cytoplasmic domain

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