Abstract
Survival following Ebola virus (EBOV) infection correlates with the ability to mount an early and robust interferon (IFN) response. The host IFN-induced proteins that contribute to controlling EBOV replication are not fully known. Among the top genes with the strongest early increases in expression after infection in vivo is IFN-induced HERC5. Using a transcription- and replication-competent VLP system, we showed that HERC5 inhibits EBOV virus-like particle (VLP) replication by depleting EBOV mRNAs. The HERC5 RCC1-like domain was necessary and sufficient for this inhibition and did not require zinc finger antiviral protein (ZAP). Moreover, we showed that EBOV (Zaire) glycoprotein (GP) but not Marburg virus GP antagonized HERC5 early during infection. Our data identify a novel ‘protagonist–antagonistic’ relationship between HERC5 and GP in the early stages of EBOV infection that could be exploited for the development of novel antiviral therapeutics.
Highlights
Ebola virus (EBOV) is a member of the Filoviridae family of single-stranded negativesense RNA viruses with a filamentous morphology
To determine if HECT and RCC1-like containing domain 5 (HERC5) restricts EBOV particle production and replication, we used an EBOV (Zaire) transcription- and replication-competent virus-like particle (VLP) system. This system utilizes a tetracistronic minigenome (‘4cis’) carrying a luciferase reporter gene together with VP40, VP24, and GP (Figure 1A) [40,45]. The advantage of this system over conventional VLP assays is that the viral proteins VP40, GP and VP24 are encoded by the minigenome and expressed from the EBOV promoter in a more natively regulated fashion [40]
We showed that HERC5 inhibits EBOV VLP replication via a novel E3 ligase-independent mechanism
Summary
Ebola virus (EBOV) is a member of the Filoviridae family of single-stranded negativesense RNA viruses with a filamentous morphology. Human studies carried out during the 2013–2016 outbreak, showed that EBOV exposure results in an early and robust immune response, largely characterized by the up-regulation of IFN-stimulated genes [2,3,4,5,6,7,8,9,10,11,12]. A contributing factor to the pathophysiology of EBOV infection is the ability of the virus to evade the host IFN response [7,13,14,15,16]. Using in vitro models of infection, it was shown that EBOV is able to evade the innate immune response through various IFN antagonisms, notably involving VP24 and VP35 proteins [17,18,19]. The key mediators of this early cellular IFN response to EBOV and how EBOV withstands this early response are not fully characterized
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