Immune Regulation and Dissemination

In vitro R78 deletion mutant RCMV replicated with 10-100 fold lower efficiency than wildtype virus, and fibroblast infected with the R78 deletion virus developed a syncytium like appearance which was not observed in wildtype RCMV infected fibroblasts. In vivo the R78 deletion virus replicated and disseminated similar to or slightly less when compared to wildtype virus but showed a reduced virulence. This manifested itself in a lower mortality of R78 deletion mutant than wildtype virus infected immune compromised rats. In vitro, an M78 deletion mutant virus replicated with 50 fold lower efficiency than wildtype virus in IC21 macrophages infected under low multiplicity. However, the replication defect was not significant under high multiplicity or in infected fibroblasts. In vivo, in both immune competent and immunocompromised mice, M78 deletion mutant MCMV replicated and/or disseminated to a lower level in the spleen and liver, and persistently infected salivary glands revealed a 100 fold reduction in titer relative to the wildtype virus.  

In vitro MCK knockout virus has been shown to replicate as well as wildtype virus. 

following inoculation into BALB/c mice, MCK knockout virus grew as well as wildtype 

Over the last several years we have started to learn that chemokine mimicry by herpesvirus is common and important for the virus. What has come as a surprise is that herpesvirus encoded chemokines and chemokine receptors have positive effects and are not only used by the virus to block the chemokine system or evade the host immune response. Accordingly it seems inevitable that these pro-inflammatory chemokine elements play imporant roles in viral growth and dissemination in vivo. 

Special thanks Ed Mocarski and Tim Sparer for thorough reading of this manuscript and for many helpful comments. This study was supported by an Alfred Benzon Foundation fellowship to Thomas Kledal. 

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