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Article

Activation of Stress Response Pathways Promotes Formation of Antiviral Granules and Restricts Virus Replication

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Pages 2003-2016 | Received 09 Dec 2013, Accepted 13 Mar 2014, Published online: 20 Mar 2023
 

Abstract

The formation of protein-RNA granules is a part of both natural cellular function (P-bodies and nuclear HNRNPs) and the response to cellular stress (stress granules and ND10 bodies). To better understand the role of stress-induced granules in viral infection, we have studied the ability of cells to restrict poxvirus replication through the formation of antiviral granules (AVGs). Of cells infected with a wild-type poxvirus, a small number spontaneously formed AVGs. In these AVG-positive cells, viral gene expression was inhibited. The addition of compounds that altered RNA helicase activity, induced oxidative stress, or stimulated translation initiation factor phosphorylation significantly increased the number of AVG-positive cells. When AVGs formed, both viral translation and titers were decreased even when host translation persisted. Treatment with the antiviral compound isatin β-thiosemicarbazone (IBT), a compound that was used to treat smallpox infections, induced AVGs, suggesting a role for these structures in the pharmacological inhibition of poxvirus replication. These findings provide evidence that AVGs are an innate host response that can be exogenously stimulated to combat virus infection. Since small molecules are able to stimulate AVG formation, it is a potential target for new antiviral development.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01630-13.

ACKNOWLEDGMENTS

We thank Doug Grosenbach, (Siga Technologies, Corvallis, OR) for providing ST-246 and Jerry Pelletier (McGill University, Montreal, Quebec, Canada) for the kind gift of hippuristanol. We thank John Porco and Neil Lajkiewicz (Department of Chemistry, Boston University) for generously providing a sample of the rocaglate rohinitib (RHT).

We appreciate David Center of the Clinical and Translational Science Institute (CTSI) for providing funds through NIH grant UL1-TR000157 for use at the Boston University Cellular Imaging Core. D.K.R. was supported by an NIH training grant in immunology to Boston University (grant 5T32AI 7309). C.M.F. was additionally supported by the NIH Program in Inflammatory Disorders at Boston University (grant T32 AI 89673-3). This work was supported by NIH grants RO1AI1096159-01 and K22AI-064606 (to J.H.C.).

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