Molecular Determinants of Ebola Virus Virulence in Mice

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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. Zaire ebolavirus causes severe hemorrhagic fever in humans with up to 90% case-fatality rates. Currently, there are no vaccines or specific therapeutic interventions available for this devastating viral disease due, at least in part, to a lack of knowledge regarding the molecular basis of virulence for this extremely pathogenic agent. While adult mice resist wild-type Zaire ebolavirus infection, the virus has recently been adapted to cause lethal infection in mice. In order to understand the pathogenesis underlying Zaire ebolavirus infection, the authors identified the mutations responsible for the acquisition of virulence in mice, using reverse genetics technology, which allows the generation of genetically altered mutant viruses from cloned cDNA. By testing the virulence of mutant viruses, two viral proteins, viral protein 24 and the nucleoprotein, were found to be primarily responsible for the acquisition of virulence in mice. Moreover, the role of these proteins in virulence correlated with their ability to confer resistance to interferon-stimulated antiviral responses in mouse cells. These findings suggest a critical role of these proteins in overcoming the interferon-induced antiviral state in the pathogenicity of Zaire ebolavirus and offer new insights into the pathogenesis of Zaire ebolavirus infection.