title: Liver sinusoidal endothelial cells are a site of murine cytomegalovirus latency and reactivation.
abstract: Latent cytomegalovirus (CMV) is frequently transmitted by organ transplantation, and its reactivation under conditions of immunosuppressive prophylaxis against graft rejection by host-versus-graft disease bears a risk of graft failure due to viral pathogenesis. CMV is the most common cause of infection following liver transplantation. Although hematopoietic cells of the myeloid lineage are a recognized source of latent CMV, the cellular sites of latency in the liver are not comprehensively typed. Here we have used the BALB/c mouse model of murine CMV infection to identify latently infected hepatic cell types. We performed sex-mismatched bone marrow transplantation with male donors and female recipients to generate latently infected sex chromosome chimeras, allowing us to distinguish between Y-chromosome (gene sry or tdy)-positive donor-derived hematopoietic descendants and Y-chromosome-negative cells of recipients' tissues. The viral genome was found to localize primarily to sry-negative CD11b(-) CD11c(-) CD31(+) CD146(+) cells lacking major histocompatibility complex class II antigen (MHC-II) but expressing murine L-SIGN. This cell surface phenotype is typical of liver sinusoidal endothelial cells (LSECs). Notably, sry-positive CD146(+) cells were distinguished by the expression of MHC-II and did not harbor latent viral DNA. In this model, the frequency of latently infected cells was found to be 1 to 2 per 10(4) LSECs, with an average copy number of 9 (range, 4 to 17) viral genomes. Ex vivo-isolated, latently infected LSECs expressed the viral genes m123/ie1 and M122/ie3 but not M112-M113/e1, M55/gB, or M86/MCP. Importantly, in an LSEC transfer model, infectious virus reactivated from recipients' tissue explants with an incidence of one reactivation per 1,000 viral-genome-carrying LSECs. These findings identified LSECs as the main cellular site of murine CMV latency and reactivation in the liver.
authors.affiliation: Institute for Virology, University Medical Center of the Johannes Gutenberg University, Hochhaus am Augustusplatz, 55131 Mainz, Germany.
authors.forename: Christof K
authors.initials: CK
authors.lastname: Seckert
authors.forename: Angélique
authors.initials: A
authors.lastname: Renzaho
authors.forename: Hanna-Mari
authors.initials: HM
authors.lastname: Tervo
authors.forename: Claudia
authors.initials: C
authors.lastname: Krause
authors.forename: Petra
authors.initials: P
authors.lastname: Deegen
authors.forename: Birgit
authors.initials: B
authors.lastname: Kühnapfel
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Reddehase
authors.forename: Natascha K A
authors.initials: NK
authors.lastname: Grzimek
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000821:virology*; D005260:Female; D020869:Gene Expression Profiling; D005814:Genes, Viral; D008099:Liver / Q000821:virology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000502:physiology*; D014775:Virus Activation; D017735:Virus Latency