Abstract
Zaire ebolavirus (ZEBOV) causes severe hemorrhagic fever in humans and nonhuman primates, with fatality rates in humans of up to 90%. The molecular basis for the extreme virulence of ZEBOV remains elusive. While adult mice resist ZEBOV infection, the Mayinga strain of the virus has been adapted to cause lethal infection in these animals. To understand the pathogenesis underlying the extreme virulence of Ebola virus (EBOV), here we identified the mutations responsible for the acquisition of the high virulence of the adapted Mayinga strain in mice, by using reverse genetics. We found that mutations in viral protein 24 and in the nucleoprotein were primarily responsible for the acquisition of high virulence. Moreover, the role of these proteins in virulence correlated with their ability to evade type I interferon-stimulated antiviral responses. These findings suggest a critical role for overcoming the interferon-induced antiviral state in the pathogenicity of EBOV and offer new insights into the pathogenesis of EBOV infection.
Highlights
Zaire ebolavirus (ZEBOV), a member of the family Filoviridae, genus Ebolavirus, causes severe hemorrhagic fever in humans and nonhuman primates (NHPs)
These mutations may have been acquired during three consecutive passages in the brains of newborn mice and/or two passages in Vero E6 cells [14]. Three of these mutations resulted in amino acid changes in the glycoprotein (GP), while the fourth created a silent mutation in the open reading frame (ORF) encoding VP40 (Figure 1A and 1B)
We have identified molecular determinants of ZEBOV virulence in mice by using reverse genetics
Summary
Zaire ebolavirus (ZEBOV), a member of the family Filoviridae, genus Ebolavirus, causes severe hemorrhagic fever in humans and nonhuman primates (NHPs). Case-fatality rates for ZEBOV infection in humans are the highest among known viral hemorrhagic fevers, ranging from 70% to 90% [1,2,3]. On the basis of in vitro data, three Ebola virus (EBOV) proteins, the glycoprotein (GP) [4,5,6], the membrane-associated viral protein (VP) 24 [7,8], and VP35 [9,10], a component of the replication complex, are thought to play key roles in EBOV pathogenicity. VP24 and VP35 are known as type I interferon (IFN) antagonists and interfere with the type I IFN-mediated antiviral response in vitro [7,9,10]. The role of these proteins in viral pathogenicity has not been determined in vivo
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