The Ebola Virus Glycoprotein Contributes to but Is Not Sufficient for Virulence In Vivo

PLoS Pathogens

Astrid Herwig¹  Andrea Marzi²  Heinz Feldmann²  Allison Groseth³  Don Gardner³  Hideki Ebihara³  Thomas Hoenen⁴  Stephan Becker⁴ 

[1] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada;Institut für Virologie, Philipps Universität Marburg, Marburg, Germany;Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America;Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada

关键词: Ebola virus;    Cloning;    Ebola hemorrhagic fever;    Pathogenesis;    Spleen;    Animal models of infection;    DNA recombination;    Viral pathogens;   

DOI  :  10.1371/journal.ppat.1002847

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Among the Ebola viruses most species cause severe hemorrhagic fever in humans; however, Reston ebolavirus (REBOV) has not been associated with human disease despite numerous documented infections. While the molecular basis for this difference remains unclear, in vitro evidence has suggested a role for the glycoprotein (GP) as a major filovirus pathogenicity factor, but direct evidence for such a role in the context of virus infection has been notably lacking. In order to assess the role of GP in EBOV virulence, we have developed a novel reverse genetics system for REBOV, which we report here. Together with a previously published full-length clone for Zaire ebolavirus (ZEBOV), this provides a unique possibility to directly investigate the role of an entire filovirus protein in pathogenesis. To this end we have generated recombinant ZEBOV (rZEBOV) and REBOV (rREBOV), as well as chimeric viruses in which the glycoproteins from these two virus species have been exchanged (rZEBOV-RGP and rREBOV-ZGP). All of these viruses could be rescued and the chimeras replicated with kinetics similar to their parent virus in tissue culture, indicating that the exchange of GP in these chimeric viruses is well tolerated. However, in a mouse model of infection rZEBOV-RGP demonstrated markedly decreased lethality and prolonged time to death when compared to rZEBOV, confirming that GP does indeed contribute to the full expression of virulence by ZEBOV. In contrast, rREBOV-ZGP did not show any signs of virulence, and was in fact slightly attenuated compared to rREBOV, demonstrating that GP alone is not sufficient to confer a lethal phenotype or exacerbate disease in this model. Thus, while these findings provide direct evidence that GP contributes to filovirus virulence in vivo, they also clearly indicate that other factors are needed for the acquisition of full virulence.

【 授权许可】

CC BY