Project A3 - Rift Valley fever virus and the DNA damage response
Prof. Dr. Friedemann Weber
Department of Virology
Faculty of Veterinary Medicine
Justus Liebig University Giessen
Biomedizinisches Forschungszentrum Seltersberg (BFS)
Tel.: +49 641 99 38350
- Project description
Background: Rift Valley fever virus (RVFV) is a mosquito-borne arbovirus (Genus Phlebovirus, Family Phenuiviridae) that causes regular and devastating epidemics in Africa. A typical RVFV outbreak kills thousands of cattle or sheep and hundreds of humans. In pregnant ruminants, the virus causes so-called “abortion storms” and the death of approximately 100% of newborn animals. In adult animals and hospitalized RVFV patients, mortality is about 10-20%. RVFV is manly transmitted by several mosquito and sandfly species but also by aerosols or contact with infected material. Moreover, the virus is able to infect a wide range of animals and can rapidly expand to new geographic areas. RVFV infection is therefore classified as a notifiable disease.
The so-called NSs protein is the main virulence factor of RVFV, blocking both induction and action of the antiviral type I interferons (IFN). We could show that both of these NSs activities are mediated through the recruitment of cellular E3 ubiquitin ligases of the F-box type. To suppress IFN induction, NSs binds the F-box protein FBXO3, which in turn initiates proteasomal degradation of the general host cell transcription factor TFIIH-p62. To suppress IFN action, NSs recruits two other host factors that are homologs of each other, FBXW11 und b-TRCP1. These F-box proteins are necessary for the NSs-mediated degradation of the antiviral kinase PKR, again via the proteasome.
Infections with RVFV trigger a DNA damage response (DDR), but without actually damaging the cellular DNA. Moreover, we could identify an interaction of a RVFV host cell factor with components of the DDR. In our project, we will investigate the interplay of RVFV infection and the DDR and test whether specific inhibitors could lower the virulence of RVFV. Moreover, we want to test additional inhibitors of the DRUID consortium against RVFV.