Yellow Fever Virus Induces Golgi Stress and CREB3L1 Nuclear Translocation in Human A549 Cells

Yellow fever is an endemic disease in Africa and South America caused by the homonymous flavivirus (YFV). The disease can manifest as a febrile syndrome and, in the most severe cases, liver failure and death. Although it can be prevented by a vaccine, there is no specific treatment. Recent studies have reported a Golgi stress response following infection with other flaviviruses such as DENV or ZIKV. Here, we investigated the effects of YFV infection on the phenotype of the Golgi apparatus and the consequences of drugs that affect Golgi function in YFV replication using the human lung cancer cell line A549. We found that YFV infection causes both fragmentation of the Golgi apparatus and dispersion of the ER-Golgi intermediate compartment. Furthermore, our results showed that YFV infection increases the expression and nuclear translocation of the transcription factor CREB3L1, which is associated with the unfolded protein response and Golgi expansion. Treatment with monensin, either before or after infection, significantly reduced viral replication. This reduction was independent of IFN-Iβ secretion. Interestingly, treatment with rosuvastatin also led to a significant reduction in viral replication, but only when administered before infection. The present study is the first demonstration of a Golgi response to YFV infection and highlights a mechanism that could be targeted by future antiviral therapeutic strategies.