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Journal of Virology, February 2006, p. 2019-2033, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.2019-2033.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Reovirus Induces and Benefits from an Integrated Cellular Stress Response

Jennifer A. Smith,1 Stephen C. Schmechel,2 Arvind Raghavan,1,{dagger} Michelle Abelson,1,{ddagger} Cavan Reilly,3 Michael G. Katze,4 Randal J. Kaufman,5 Paul R. Bohjanen,1,6 and Leslie A. Schiff1*

Department of Microbiology,1 Division of Biostatistics,3 Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455,6 Departments of Pathology,2 Microbiology, University of Washington Medical School, Seattle, Washington 98195,4 Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 481095

Received 4 October 2005/ Accepted 22 November 2005

Following infection with most reovirus strains, viral protein synthesis is robust, even when cellular translation is inhibited. To gain further insight into pathways that regulate translation in reovirus-infected cells, we performed a comparative microarray analysis of cellular gene expression following infection with two strains of reovirus that inhibit host translation (clone 8 and clone 87) and one strain that does not (Dearing). Infection with clone 8 and clone 87 significantly increased the expression of cellular genes characteristic of stress responses, including the integrated stress response. Infection with these same strains decreased transcript and protein levels of P58IPK, the cellular inhibitor of the eukaryotic initiation factor 2{alpha} (eIF2{alpha}) kinases PKR and PERK. Since infection with host shutoff-inducing strains of reovirus impacted cellular pathways that control eIF2{alpha} phosphorylation and unphosphorylated eIF2{alpha} is required for translation initiation, we examined reovirus replication in a variety of cell lines with mutations that impact eIF2{alpha} phosphorylation. Our results revealed that reovirus replication is more efficient in the presence of eIF2{alpha} kinases and phosphorylatable eIF2{alpha}. When eIF2{alpha} is phosphorylated, it promotes the synthesis of ATF4, a transcription factor that controls cellular recovery from stress. We found that the presence of this transcription factor increased reovirus yields 10- to 100-fold. eIF2{alpha} phosphorylation also led to the formation of stress granules in reovirus-infected cells. Based on these results, we hypothesize that eIF2{alpha} phosphorylation facilitates reovirus replication in two ways—first, by inducing ATF4 synthesis, and second, by creating an environment that places abundant reovirus transcripts at a competitive advantage for limited translational components.

* Corresponding author. Mailing address: Department of Microbiology, University of Minnesota, 420 Delaware Street SE, MMC 196, Minneapolis, MN 55455. Phone: (612) 624-9933. Fax: (612) 626-0623. E-mail: schif002{at}umn.edu.

{dagger} Present address: Minneapolis Medical Research Foundation, Minneapolis, MN 55404.

{ddagger} Present address: ViroMed Laboratories, Minnetonka, MN 55343.

Journal of Virology, February 2006, p. 2019-2033, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.2019-2033.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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