title: A shutoff and exonuclease mutant of murine gammaherpesvirus-68 yields infectious virus and causes RNA loss in type I interferon receptor knockout cells.
abstract: Significant loss of RNA followed by severely reduced cellular protein pool, a phenomenon termed host shutoff, is associated with a number of lytic virus infections and is a critical player in viral pathogenesis. Until recently, viral DNA exonucleases were associated only with processing of viral genomic DNA and its encapsidation. However, recent observations have identified host shutoff and exonuclease function for the highly conserved viral exonucleases in γ-herpesviruses, which include Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus and the mouse model murine gammaherpesvirus-68, also referred to as MHV-68. In this study, we show that although ablation of the MHV-68 exonuclease ORF37 caused a restrictive phenotype in WT IFN-α/β receptor-positive cells such as NIH 3T3, lack of ORF37 was tolerated in cells lacking the IFN-α/β receptor: the ORF37Stop virus was capable of forming infectious particles and caused loss of mRNA in IFN-α/β receptor knockout cells. Moreover, ORF37Stop virus was able to establish lytic infection in the lungs of mice lacking the IFN-α/β receptor. These observations provide evidence that lytic MHV-68 infection and subsequent loss of mRNA can take place independently of ORF37. Moreover, efficient growth of ORF37Stop virus also identifies a role for this family of viral nucleases in providing a window of opportunity for virus growth by overcoming type I IFN-dependent responses.
authors.affiliation: Department of Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sheridan
authors.affiliation: Department of Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Polychronopoulos
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
authors.forename: Bernadette M
authors.initials: BM
authors.lastname: Dutia
authors.affiliation: Department of Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK.
authors.forename: Bahram
authors.initials: B
authors.lastname: Ebrahimi
mesh_terms: D000818:Animals; D002460:Cell Line; D005092:Exonucleases / Q000172:deficiency* / Q000235:genetics; D055786:Gene Knockout Techniques; D008168:Lung / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000235:genetics; D017464:Receptors, Complement 3d; D018144:Rhadinovirus / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D017464:Receptors, Complement 3d; D014764:Viral Proteins; D053633:Receptor, Interferon alpha-beta; D005092:Exonucleases