As a tick-borne, zoonotic, emerging virus, Crimean-Congo hemorrhagic fever virus (CCHFV) poses a serious threat to public health. It is responsible in humans for a hemorrhagic disease with a mortality rate of 10-40%, with no specic treatment or vaccine. To date, the interactions between CCHFV and innate immunity are poorly understood. Notably, type I interferon (IFN) has a crucial role in the establishment of an antiviral state against CCHFV, probably through the transcription of IFNstimulated genes (ISGs) with antiviral properties. However, it remains to be determined which ISGs modulate CCHFV infection and their mechanisms of action.
To address these questions, we performed a gain-of-function screen using CCHFV virus-like particles competent for entry and transcription of a reporter minigenome (tc-VLPs), a BSL-2 model of CCHFV, and lentiviral vectors encoding >500 human, >350 simian and >250 bovine individual cDNAs of ISGs. We identied several ISGs that modulate either negatively or positively tc-VLPs infection and that were previously undescribed in the context of CCHFV infection. To dene their mechanisms of action, we dissected their impact on the dierent steps of the viral life cycle using various assays.We identied ISGs inhibiting the step of viral entry and a GTP-binding protein that promotes tc-VLP replication and/or transcription. Moreover, the eects of the overexpression of the ISGs were studied in the context of wild-type virus infection in BSL-4 conditions.
Collectively, these results provide new data on the interaction of CCHFV with host innate immune response components and pave the way for therapeutic countermeasures.