title: Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection.
abstract: Gammaherpesviruses establish persistent, systemic infections and cause cancers. Murid herpesvirus 4 (MuHV-4) provides a unique window into the early events of host colonization. It spreads via lymph nodes. While dendritic cells (DC) pass MuHV-4 to lymph node B cells, subcapsular sinus macrophages (SSM), which capture virions from the afferent lymph, restrict its spread. Understanding how this restriction works offers potential clues to a more comprehensive defense. Type I interferon (IFN-I) blocked SSM lytic infection and reduced lytic cycle-independent viral reporter gene expression. Plasmacytoid DC were not required, but neither were SSM the only source of IFN-I, as IFN-I blockade increased infection in both intact and SSM-depleted mice. NK cells restricted lytic SSM infection independently of IFN-I, and SSM-derived virions spread to the spleen only when both IFN-I responses and NK cells were lacking. Thus, multiple innate defenses allowed SSM to adsorb virions from the afferent lymph with relative impunity. Enhancing IFN-I and NK cell recruitment could potentially also restrict DC infection and thus improve infection control.
  
  
  
  Human gammaherpesviruses cause cancers by infecting B cells. However, vaccines designed to block virus binding to B cells have not stopped infection. Using a related gammaherpesvirus of mice, we have shown that B cells are infected not via cell-free virus but via infected myeloid cells. This suggests a different strategy to stop B cell infection: stop virus production by myeloid cells. Not all myeloid infection is productive. We show that subcapsular sinus macrophages, which do not pass infection to B cells, restrict gammaherpesvirus production by recruiting type I interferons and natural killer cells. Therefore, a vaccine that speeds the recruitment of these defenses might stop B cell infection.
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: 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: Instituto de Medicina Molecular e Instituto de Microbiologia, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: J Pedro
authors.initials: JP
authors.lastname: Simas
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland and Royal Children's Hospital, Brisbane, Australia p.stevenson@uq.edu.au.
authors.forename: Philip G
authors.identifier: 0000-0002-3520-5060
authors.initials: PG
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D006566:Herpesviridae Infections / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology* / Q000821:virology*; D008264:Macrophages / Q000276:immunology / Q000821:virology; D051379:Mice; D018144:Rhadinovirus / Q000276:immunology*; D014412:Tumor Virus Infections / Q000276:immunology*
chemical_list: D007370:Interferon Type I