Henipaviruses are zoonotic paramyxoviruses causing severe neurological and respiratory disease in human and are associated with a ~60% mortality rate. Hendra virus (HeV) is transmitted from bats to horses and infected horses then spread the virus to humans. Nipah virus (NiV) is transmitted to humans via diseased pigs or in some cases directly from bats. There is currently no approved treatment or vaccine against these emerging viruses. A RNA interference whole genome screen performed by our group identified several host genes required for HeV and NiV replication. Temporal modulation of host gene expression leading to the inhibition of viral replication represents a novel avenue for antiviral development. Amongst the top candidates identified in the screen the nucleolar protein fibrillarin greatly reduced HeV and NiV replication in human cells as measured by TCID50 and antigen staining. The nucleolus is a subnuclear structure and two of its major components, fibrillarin and nucleolin, are involved in nucleolar assembly, ribosome biogenesis, cell cycle regulation, cell proliferation and can act as chaperones for the import of proteins into the nucleolus. Fibrillarin has previously been shown to interact with viral proteins such as the coronavirus nucleoprotein and influenza nonstructural protein 1 (NS1), and NS1 inhibits host cell pre-mRNA processing via its association with fibrillarin, nucleolin and B23. The matrix (M) protein from Newcastle disease virus and NS1 from respiratory syncytial virus, two members of the Paramyxoviridae family, have been found in the nucleus. HeV and NiV M protein as well as the accessory protein W localize in or transit through the nucleus during infection. Therefore, we are currently investigating the essential role of fibrillarin in HeV life cycle and its possible interaction with HeV proteins. Furthermore, we are exploring the impact of knocking down fibrillarin expression on the replication of viruses belonging to different families.