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Journal of Virology, July 2009, p. 6987-6994, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.00585-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Variation in Antagonism of the Interferon Response to Rotavirus NSP1 Results in Differential Infectivity in Mouse Embryonic Fibroblasts{triangledown}

N. Feng,1 A. Sen,1 H. Nguyen,1 P. Vo,1 Y. Hoshino,2 E. M. Deal,1 and H. B. Greenberg1*

Stanford University, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California,1 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland2

Received 20 March 2009/ Accepted 27 April 2009

Rotavirus NSP1 has been shown to function as an E3 ubiquitin ligase that mediates proteasome-dependent degradation of interferon (IFN) regulatory factors (IRF), including IRF3, -5, and -7, and suppresses the cellular type I IFN response. However, the effect of rotavirus NSP1 on viral replication is not well defined. Prior studies used genetic analysis of selected reassortants to link NSP1 with host range restriction in the mouse, suggesting that homologous and heterologous rotaviruses might use their different abilities to antagonize the IFN response as the basis of their host tropisms. Using a mouse embryonic fibroblast (MEF) model, we demonstrate that heterologous bovine (UK and NCDV) and porcine (OSU) rotaviruses fail to effectively degrade cellular IRF3, resulting in IRF3 activation and beta IFN (IFN-β) secretion. As a consequence of this failure, replication of these viruses is severely restricted in IFN-competent wild-type, but not in IFN-deficient (IFN-{alpha}/β/{gamma} receptor- or STAT1-deficient) MEFs. On the other hand, homologous murine rotaviruses (ETD or EHP) or the heterologous simian rotavirus (rhesus rotavirus [RRV]) efficiently degrade cellular IRF3, diminish IRF3 activation and IFN-β secretion and are not replication restricted in wild-type MEFs. Genetic reassortant analysis between UK and RRV maps the distinctive phenotypes of IFN antagonism and growth restriction in wild-type MEFs to NSP1. Therefore, there is a direct relationship between the replication efficiencies of different rotavirus strains in MEFs and strain-related variations in NSP1-mediated antagonism of the type I IFN response.

* Corresponding author. Mailing address: VA Palo Alto Health Care System, 3801 Miranda Ave. MC154C, Palo Alto, CA 94304. Phone: (650) 752-9722. Fax: (650) 852-3259. E-mail: hbgreen{at}stanford.edu

{triangledown} Published ahead of print on 6 May 2009.

Journal of Virology, July 2009, p. 6987-6994, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.00585-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sen, A., Feng, N., Ettayebi, K., Hardy, M. E., Greenberg, H. B. (2009). IRF3 Inhibition by Rotavirus NSP1 Is Host Cell and Virus Strain Dependent but Independent of NSP1 Proteasomal Degradation. J. Virol. 83: 10322-10335 [Abstract] [Full Text]  


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