Roles for Virus-Induced RNA Turnover in Pathogenesis

mouse sniffing flask of viruses

Many viruses are known to restrict host gene expression via a variety of different mechanisms.  While proposed to facilitate immune evasion and to aid in the reallocation of cellular resources towards viral replication, in very few cases has the role of this specific phenotype during in vivo infection of a host been directly evaluated.  Within the gammaherpesviruses, we have shown host shutoff to be a conserved phenotype, which, similar to KSHV, is executed by the SOX homologs BGLF5 within Epstein-Barr virus (EBV) and muSOX in murine gammaherpesvirus 68 (MHV68) (Rowe et al., 2007, PNAS 104(9):3366; Covarrubias et al., 2009, J. Virol., 83(18):9554).  While both KSHV and EBV are associated with significant human disease, they are difficult to genetically manipulate and the potential for in vivo studies is limited because of their strict species specificity.  MHV68 possesses significantly more tractable genetics and has proven to be a robust tool for the study of gammaherpesvirus pathogenesis.  In collaboration with Laurent Coscoy in the Division of Immunology at UC Berkeley, we are using MHV68 to examine the role of SOX-induced mRNA degradation in the in vivo pathogenesis of gammaherpesviruses.

To specifically evaluate the role of mRNA turnover during gammaherpesvirus infection, we engineered a variant of MHV68 bearing a muSOX point mutant selectively defective in its ability to promote mRNA turnover. Unexpectedly, the mutant virus showed little defect during the acute replication phase in cultured 3T3 cells or in the mouse lung.  However, it exhibited profound attenuation at later stages of in vivo infection suggestive of defects in both virus trafficking and latency establishment.  Specifically, mice infected with the host shutoff mutant accumulated to lower levels in the lymph nodes, failed to develop splenomegaly, and exhibited reduced viral DNA levels and a dramatically lower frequency of latently infected splenocytes (Richner et al., 2011, July 21; 7(7): e1002150).  These findings highlight for the first time the importance of global mRNA degradation during a gammaherpesvirus infection and link an exclusively lytic phenomenon with downstream latency-associated events.  We are currently working towards understanding the mechanistic basis for these defects.