Proteins of the secretory pathway govern virus productivity during lytic gammaherpesvirus infection

Background: Diseases caused by gammaherpesviruses continue to be a challenge for human health and antiviral treatment. Most of the commonly used antiviral drugs are directed against viral gene products. However, the emergence of drug-resistant mutations ma limit the effectiveness of these drugs. Since viruses require a host cell to propagate, the search for host cell targets is an interestin alternative. Methods: In this study, we infected three different cell types (fibroblasts, endothelial precursor cells and macrophages with a murine gammaherpesvirus and analysed the host cell response for changes either common to all or unique to a particular cell type using oligonucleotide microarrays. Results: The analysis revealed a number of genes whose transcription was significantly up- or down-regulated in either one or two of the cell types tested. After infection, only two genes, Lman1 (also known as ERGIC53) an synaptobrevin-like 1 (sybl1) were significantly up-regulated in all three cell types, suggestive for a general role for the virus life cycl independent of the cell type. Both proteins have been implicated in cellular exocytosis and transport of glycoproteins through the secre tory pathway. To test the significance of the observed up-regulation, the functionality of these proteins was modulated, and the effect on virus replication was monitored. Inhibition of either Lman1 or sybl1 resulted in a significant reduction in virus production. Conclusions: This suggests that proteins of the secretory pathway which appear to be rate limiting for virus production may represent new targets for intervention.