Abstract
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.
Highlights
Herpesviruses are characterized by their ability to establish a lifelong latent infection in their natural host and reactivate upon immunosuppression
We show that the inhibition of MCMV replication by IFNb depends on the inhibition of viral gene expression at the level of immediate early (IE) transcription mediated by nuclear domain 10 (ND10) components, which is fully reversible even after extended culture of in vitro infected cells and in cultures of endothelial cells derived from latently infected mice
To study type I interferon (IFN) effects on MCMV replication in quiescent liver sinusoidal endothelial cells (LSECs), growth-arrested cells were incubated with IFNb for 24 h, infected with MCMV at a multiplicity of infection (MOI) of 0.001 and viral growth was assayed for a week
Summary
Herpesviruses are characterized by their ability to establish a lifelong latent infection in their natural host and reactivate upon immunosuppression. Cytomegaloviruses (CMV) are paradigmatic b-herpesviruses, characterized by strict species specificity, but highly prevalent in numerous mammalian species [1]. Human CMV (HCMV) prevalence ranges from 30 to 90% [2]. While primary infection and latency are usually asymptomatic in immunocompetent individuals, immune suppression results in virus reactivation, which is associated with substantial morbidity and mortality. CMV reactivation may result in allograft rejection, pneumonia or gastroenteritis in recipients of solid-organ and bone-marrow transplants [3]. Understanding the molecular mechanisms involved in the establishment and maintenance of latency is fundamental for developing effective countermeasures to CMV disease in high-risk populations
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