title: Activation of stress response pathways promotes formation of antiviral granules and restricts virus replication.
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.
authors.affiliation: Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Rozelle
authors.forename: Claire Marie
authors.initials: CM
authors.lastname: Filone
authors.forename: Nancy
authors.initials: N
authors.lastname: Kedersha
authors.forename: John H
authors.initials: JH
authors.lastname: Connor
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000821:virology*; D004265:DNA Helicases; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007510:Isatin / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D000075223:Poly-ADP-Ribose Binding Proteins; D014176:Protein Biosynthesis / Q000235:genetics; D020365:RNA Helicases / Q000378:metabolism; D000067776:RNA Recognition Motif Proteins; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D013312:Stress, Physiological; D014615:Vaccinia / Q000821:virology*; D014616:Vaccinia virus / Q000502:physiology*; D014779:Virus Replication
chemical_list: D002352:Carrier Proteins; D039642:Eukaryotic Initiation Factors; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D012333:RNA, Messenger; D012367:RNA, Viral; C013578:isatin beta-thiosemicarbazone; D007510:Isatin; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases