Molecular determinants of Ebola virus virulence in mice.
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.
Ebihara
Hideki
H
Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Takada
Ayato
A
Kobasa
Darwyn
D
Jones
Steven
S
Neumann
Gabriele
G
Theriault
Steven
S
Bray
Mike
M
Feldmann
Heinz
H
Kawaoka
Yoshihiro
Y
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D029043:Ebolavirus / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D009698:Nucleoproteins / Q000235:genetics; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics*
D000998:Antiviral Agents; D007370:Interferon Type I; D009698:Nucleoproteins; C446938:VP24 protein, Ebola virus; D014764:Viral Proteins; D037521:Virulence Factors