title: Type I Interferons Direct Gammaherpesvirus Host Colonization.
abstract: Gamma-herpesviruses colonise lymphocytes. Murid Herpesvirus-4 (MuHV-4) infects B cells via epithelial to myeloid to lymphoid transfer. This indirect route entails exposure to host defences, and type I interferons (IFN-I) limit infection while viral evasion promotes it. To understand how IFN-I and its evasion both control infection outcomes, we used Mx1-cre mice to tag floxed viral genomes in IFN-I responding cells. Epithelial-derived MuHV-4 showed low IFN-I exposure, and neither disrupting viral evasion nor blocking IFN-I signalling markedly affected acute viral replication in the lungs. Maximising IFN-I induction with poly(I:C) increased virus tagging in lung macrophages, but the tagged virus spread poorly. Lymphoid-derived MuHV-4 showed contrastingly high IFN-I exposure. This occurred mainly in B cells. IFN-I induction increased tagging without reducing viral loads; disrupting viral evasion caused marked attenuation; and blocking IFN-I signalling opened up new lytic spread between macrophages. Thus, the impact of IFN-I on viral replication was strongly cell type-dependent: epithelial infection induced little response; IFN-I largely suppressed macrophage infection; and viral evasion allowed passage through B cells despite IFN-I responses. As a result, IFN-I and its evasion promoted a switch in infection from acutely lytic in myeloid cells to chronically latent in B cells. Murine cytomegalovirus also showed a capacity to pass through IFN-I-responding cells, arguing that this is a core feature of herpesvirus host colonization.
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland and Royal Children's Hospital, Brisbane, Australia.
authors.forename: Cindy S E
authors.initials: CS
authors.lastname: Tan
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland and Royal Children's Hospital, Brisbane, Australia.
authors.forename: Clara
authors.initials: C
authors.lastname: Lawler
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Janet S
authors.initials: JS
authors.lastname: May
authors.affiliation: Molecular Immunology, Walter and Eliza Hall Institute, Parkville, Melbourne, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland and Royal Children's Hospital, Brisbane, Australia.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018142:Gammaherpesvirinae / Q000276:immunology / Q000472:pathogenicity; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D000067996:RAW 264.7 Cells
chemical_list: D007370:Interferon Type I