title: Myeloid infection links epithelial and B cell tropisms of Murid Herpesvirus-4.
abstract: Gamma-herpesviruses persist in lymphocytes and cause disease by driving their proliferation. Lymphocyte infection is therefore a key pathogenetic event. Murid Herpesvirus-4 (MuHV-4) is a rhadinovirus that like the related Kaposi's Sarcoma-associated Herpesvirus persists in B cells in vivo yet infects them poorly in vitro. Here we used MuHV-4 to understand how virion tropism sets the path to lymphocyte colonization. Virions that were highly infectious in vivo showed a severe post-binding block to B cell infection. Host entry was accordingly an epithelial infection and B cell infection a secondary event. Macrophage infection by cell-free virions was also poor, but improved markedly when virion binding improved or when macrophages were co-cultured with infected fibroblasts. Under the same conditions B cell infection remained poor; it improved only when virions came from macrophages. This reflected better cell penetration and correlated with antigenic changes in the virion fusion complex. Macrophages were seen to contact acutely infected epithelial cells, and cre/lox-based virus tagging showed that almost all the virus recovered from lymphoid tissue had passed through lysM(+) and CD11c(+) myeloid cells. Thus MuHV-4 reached B cells in 3 distinct stages: incoming virions infected epithelial cells; infection then passed to myeloid cells; glycoprotein changes then allowed B cell infection. These data identify new complexity in rhadinovirus infection and potentially also new vulnerability to intervention.
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom.
authors.forename: Bruno
authors.initials: B
authors.lastname: Frederico
authors.forename: Ricardo
authors.initials: R
authors.lastname: Milho
authors.forename: Janet S
authors.initials: JS
authors.lastname: May
authors.forename: Laurent
authors.initials: L
authors.lastname: Gillet
authors.forename: Philip G
authors.initials: PG
authors.lastname: Stevenson
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001402:B-Lymphocytes / Q000821:virology*; D039521:CD11c Antigen; D002460:Cell Line; D006224:Cricetinae; D004847:Epithelial Cells / Q000821:virology*; D005347:Fibroblasts / Q000821:virology; D057809:HEK293 Cells; D006566:Herpesviridae Infections / Q000276:immunology / Q000821:virology*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000821:virology; D018144:Rhadinovirus / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology*; D014412:Tumor Virus Infections / Q000276:immunology / Q000821:virology*; D014759:Viral Envelope Proteins / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D039521:CD11c Antigen; D014759:Viral Envelope Proteins