Global mRNA Degradation during Lytic Gammaherpesvirus Infection Contributes to Establishment of Viral Latency

PLoS Pathogens

Laurent Coscoy¹  Tina Wang¹  Andrea C. Pezda¹  Britt Glaunsinger²  G. Renuka Kumar²  Benson Yee Hin Cheng²  Justin M. Richner²  Karen Clyde²  Sergio Covarrubias³ 

[1] Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, United States of America;Department of Plant and Microbial Biology, University of California Berkeley, Berkeley, California, United States of America;Division of Infectious Diseases and Immunity, School of Public Health, University of California Berkeley, Berkeley, California, United States of America

关键词: Viral replication;    Viral persistence;    latency;    Virus effects on host gene expression;    Spleen;    Herpesviruses;    NIH 3T3 cells;    Polymerase chain reaction;    Lymph nodes;   

DOI  :  10.1371/journal.ppat.1002150

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

During a lytic gammaherpesvirus infection, host gene expression is severely restricted by the global degradation and altered 3′ end processing of mRNA. This host shutoff phenotype is orchestrated by the viral SOX protein, yet its functional significance to the viral lifecycle has not been elucidated, in part due to the multifunctional nature of SOX. Using an unbiased mutagenesis screen of the murine gammaherpesvirus 68 (MHV68) SOX homolog, we isolated a single amino acid point mutant that is selectively defective in host shutoff activity. Incorporation of this mutation into MHV68 yielded a virus with significantly reduced capacity for mRNA turnover. Unexpectedly, the MHV68 mutant showed little defect during the acute replication phase in the mouse lung. Instead, the virus exhibited attenuation at later stages of in vivo infections suggestive of defects in both trafficking and latency establishment. Specifically, mice intranasally infected with the host shutoff mutant accumulated to lower levels at 10 days post infection in the lymph nodes, failed to develop splenomegaly, and exhibited reduced viral DNA levels and a lower frequency of latently infected splenocytes. Decreased latency establishment was also observed upon infection via the intraperitoneal route. These results highlight for the first time the importance of global mRNA degradation during a gammaherpesvirus infection and link an exclusively lytic phenomenon with downstream latency establishment.

【 授权许可】

CC BY