Reversible Silencing of Cytomegalovirus Genomes by Type I Interferon Governs Virus Latency

PLoS Pathogens

Robert Geffers¹  Adrien Weingärtner²  Franziska Dağ²  Anja Drabig²  Luka Čičin-Šain²  Julia Holzki²  Ianina Conte²  Martin Messerle³  Johannes Schwerk⁴  Ulfert Rand⁴  Hansjörg Hauser⁴  Mario Köster⁴  Dagmar Wirth⁴  Lars Dölken⁵  Stefan Lienenklaus⁶  Siegfried Weiß⁶  Colin Davenport⁷  Barbara Adler⁸ 

[1] Department for Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany;Department for Vaccinology/Immune Aging and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany;Department for Virology, Medical School Hannover, Hannover, Germany;Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany;Department of Medicine, University of Cambridge, Cambridge, United Kingdom;Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany;Department of Pediatric Pneumology and Neonatology, Medical School Hannover, Hannover, Germany;Department of Virology, Max von Pettenkofer Institute, Ludwig Maximillian University, Munich, Germany

关键词: Viral replication;    Gene expression;    Viral persistence;    latency;    Viral gene expression;    Interferons;    Yellow fluorescent protein;    Human cytomegalovirus;    Cytomegalovirus infection;   

DOI  :  10.1371/journal.ppat.1003962

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY