Browsing publications of the research group immune aging and chronic infections (IMCI) by Subjects
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A new reporter mouse cytomegalovirus reveals maintained immediate-early gene expression but poor virus replication in cycling liver sinusoidal endothelial cells.The MCMV major immediate early promoter/enhancer (MIEP) is a bidirectional promoter that drives the expression of the three immediate early viral genes, namely ie1, ie2 and ie3. The regulation of their expression is intensively studied, but still incompletely understood.
Mouse CMV infection delays antibody class switch upon an unrelated virus challenge.Poor immune protection upon vaccination is a critical determinant of immunosenescence. Latent Cytomegalovirus (CMV) infection has been associated with poor antibody responses to vaccination, but a causative role for CMV in the poor immune response requires experimental evidence and thus could not be confirmed in clinical studies. To test the hypothesis that latent CMV infection causes poor antibody responses, we infected young or adult mice with mouse CMV and challenged them with Vesicular stomatitis virus (VSV) at 15 or 18months of age. Latent, but not primary infection with mouse CMV resulted in diminished neutralizing titers of the serum IgG fraction at day 7 post challenge, which recovered by day 14 post challenge. This phenomenon was specific for mice infected with mouse CMV, but not mice infected with other herpesviruses, like murine herpesvirus-68 or herpes simplex virus type 1, or mice infected with non-persistent viruses, such as influenza or Vaccinia virus. Hence, our data indicate a delay in IgG class-switch that was specific for the CMV infection. Herpesviral infections did not change the B-cell memory compartment, and increased the size of the effector-memory subset of blood CD4 T-cells only when administered in combination. Furthermore, CD4 T-cell response to VSV infection was maintained in latently infected mice. Therefore, our results argue that latent CMV infection impairs B-cell, but not T-cell responses to a challenge with VSV and delays antibody class-switch by a mechanism which may be independent of T-cell help.
A replicating cytomegalovirus-based vaccine encoding a single Ebola virus nucleoprotein CTL epitope confers protection against Ebola virus.Human outbreaks of Ebola virus (EBOV) are a serious human health concern in Central Africa. Great apes (gorillas/chimpanzees) are an important source of EBOV transmission to humans due to increased hunting of wildlife including the 'bush-meat' trade. Cytomegalovirus (CMV) is an highly immunogenic virus that has shown recent utility as a vaccine platform. CMV-based vaccines also have the unique potential to re-infect and disseminate through target populations regardless of prior CMV immunity, which may be ideal for achieving high vaccine coverage in inaccessible populations such as great apes.
Reversible silencing of cytomegalovirus genomes by type I interferon governs virus latency.Herpesviruses establish a lifelong latent infection posing the risk for virus reactivation and disease. In cytomegalovirus infection, expression of the major immediate early (IE) genes is a critical checkpoint, driving the lytic replication cycle upon primary infection or reactivation from latency. While it is known that type I interferon (IFN) limits lytic CMV replication, its role in latency and reactivation has not been explored. In the model of mouse CMV infection, we show here that IFNβ blocks mouse CMV replication at the level of IE transcription in IFN-responding endothelial cells and fibroblasts. The IFN-mediated inhibition of IE genes was entirely reversible, arguing that the IFN-effect may be consistent with viral latency. Importantly, the response to IFNβ is stochastic, and MCMV IE transcription and replication were repressed only in IFN-responsive cells, while the IFN-unresponsive cells remained permissive for lytic MCMV infection. IFN blocked the viral lytic replication cycle by upregulating the nuclear domain 10 (ND10) components, PML, Sp100 and Daxx, and their knockdown by shRNA rescued viral replication in the presence of IFNβ. Finally, IFNβ prevented MCMV reactivation from endothelial cells derived from latently infected mice, validating our results in a biologically relevant setting. Therefore, our data do not only define for the first time the molecular mechanism of IFN-mediated control of CMV infection, but also indicate that the reversible inhibition of the virus lytic cycle by IFNβ is consistent with the establishment of CMV latency.