A murid gamma-herpesviruses exploits normal splenic immune communication routes for systemic spread.
Gamma-herpesviruses (γHVs) are widespread oncogenic pathogens that chronically infect circulating lymphocytes. How they subvert the immune check-point function of the spleen to promote persistent infection is not clear. We show that Murid Herpesvirus-4 (MuHV-4) enters the spleen by infecting marginal zone (MZ) macrophages, which provided a conduit to MZ B cells. Relocation of MZ B cells to the white pulp allowed virus transfer to follicular dendritic cells. From here the virus reached germinal center B cells to establish persistent infection. Mice lacking MZ B cells, or treated with a sphingosine-1-phosphate receptor agonist to dislocate them, were protected against MuHV-4 colonization. MuHV-4 lacking ORF27, which encodes a glycoprotein necessary for efficient intercellular spread, could infect MZ macrophages but was impaired in long-term infection. Thus, MuHV-4, a γHV, exploits normal immune communication routes to spread by serial lymphoid/myeloid exchange.
Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK.
Bruno
B
Frederico
Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK.
Brittany
B
Chao
Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK.
Janet S
JS
May
Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
Gabrielle T
GT
Belz
Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK; Sir Albert Sakzewski Virus Research Centre and Queensland Children's Medical Research Institute, University of Queensland, Brisbane, Queensland 4029, Australia. Electronic address: p.stevenson@uq.edu.au.
Philip G
PG
Stevenson
D000818:Animals; D001402:B-Lymphocytes / Q000821:virology; D002460:Cell Line; D006224:Cricetinae; D020566:Dendritic Cells, Follicular / Q000821:virology*; D018858:Germinal Center / Q000166:cytology / Q000821:virology*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000635:transmission; D008264:Macrophages / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016366:Open Reading Frames / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D018144:Rhadinovirus / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000473:pathology / Q000821:virology
D049349:Receptors, Lysosphingolipid