SSA Dissecting the pro-viral functions of Jmjd6 in influenza A virus infection

Influenza A viruses (IAV) cause annual epidemics and are a major threat for public health, food security and the global economy. To replicate, the virus relies on host cell machinery to promote viral gene expression. Many studies have identified individual host proteins that support virus replication but there is still a limited understanding of how these multiple factors contribute to a successful virus life cycle. This project aims to combine cutting edge conditional in vivo gene knock-out technology with genetically modified viruses to examine the effects of removing a crucial cellular gene for virus replication in infected cells.

We have recently identified that the jumonji domain containing protein 6 (Jmjd6) is a cellular host factor essential for IAV growth. Jmjd6 is a member of the JmjC-domain containing family of 2-oxoglutarate and Fe2+-dependent dioxygenases. It is a nuclear hydroxylase that has been demonstrated to hydroxylate or demethylate transcription initiation factors, histone proteins, spliceosomal components, and heat shock factors thereby regulating host gene expression at multiple levels (for review see PMID 28360925). Using siRNA approaches we have generated JMJD6-ablated human lung carcinoma A549 cells. When infected with IAV, these cells showed drastically reduced viral replication, and reduced viral mRNA and protein expression. Binding and internalisation of IAV was found to be normal in JMJD6-knockdown cells, but nuclear import of viral ribonucleoprotein (vRNP) complexes was severely impaired. Based on these in vitro results, we thus hypothesise that Jmjd6 has a specific and essential function in an early step of IAV infection. The unusually severe phenotypic effect of JMJD6-knockdown on IAV replication (almost complete ablation of infection) makes it an attractive candidate for further development of novel antiviral strategies.