IRES Knocks out Rabies

ReseaRch highlights

viral pathogenesis IRES knocks out rabies

Non-segmented negative-strand from poliovirus or human rhinovirus Infection of neurons with RNA RNA viruses that can infect neurons type 2 (HRV2) enables downregula- viruses is initially controlled by in the central nervous system include tion of phosphoprotein expression interferon-β (IFNβ) and subsequently measles virus, mumps virus, Borna at the level of translation and can by virus-specific antibodies and virus, the emerging deadly Nipah render rabies virus avirulent. T-cell derived IFNβ. The rabies virus and Hendra viruses and rabies virus. Although rabies and other phosphoprotein, which is an essential Until now there has been no method non-segmented negative-strand cofactor of the viral polymerase and available to control the expression RNA viruses can replicate in all also has a role in encapsidation of of individual genes of these viruses. cell types, positive-strand RNA replicated genomes, functions to According to a report published in viruses, such as poliovirus and dampen the host response by coun- the Journal of Virology, replacing the HRV2, have a restricted host range. teracting the production of IFN. The transcription signals of the rabies There is evidence that IRESs in the most striking finding from this study virus phosphoprotein gene with 5′-untranslated regions of positive- is that translational attenuation of internal ribosome entry sites (IRESs) strand RNA viruses are subject to phosphoprotein through insertion of cell-type inhibition and can mediate IRESs from poliovirus or HRV2 lim- cell-type specificity. To test whether ited the ability of recombinant rabies

Corbis IRESs can affect gene expression of viruses to counteract the production non-segmented negative-strand RNA of IFN, as shown by the failure of viruses, Marschalek et al. replaced recombinant viruses to prevent tran- the transcription signals of the rabies scription of the host Ifnβ gene. The phosphoprotein gene with IRESs authors propose that the phosphopro- from poliovirus and HRV2. tein has a vital role in controlling the Using a dual reporter system that host innate immune response. inserts different luciferase reporters Although there are several upstream and downstream of the post-exposure vaccines for rabies, IRES they were able to monitor infection is almost always fatal if the the translation initiation of the virus reaches the brain. These stud- IRES elements in different cells. ies reveal that translational control Unexpectedly, they found that the of individual genes is a promising HRV2 IRES was active in all cell strategy to attenuate replication and types, including neurons. Previous virulence of live non-segmented reports had indicated that HRV2 negative-strand RNA viruses and could not replicate in neurons, unlike might provide a basis for a new the neurotropic poliovirus. In spite of vaccine formulation. this, both types of recombinant virus Susan Jones that expressed the phosphoprotein under the control of the IRES were original researCh paper Marschalek, A. avirulent in neonatal mice, whereas et al. Attenuation of rabies virus virulence and replication by picornavirus IRES elements. J. Virol. wild-type rabies virus was 100% 10 Dec 2008 (doi:10.1128/JVI.02055-08) lethal.