Less is more: Ebola virus surface glycoprotein expression levels regulate virus production and infectivity.
The Ebola virus (EBOV) surface glycoprotein (GP1,2) mediates host cell attachment and fusion and is the primary target for host neutralizing antibodies. Expression of GP1,2 at high levels disrupts normal cell physiology, and EBOV uses an RNA-editing mechanism to regulate expression of the GP gene. In this study, we demonstrate that high levels of GP1,2 expression impair production and release of EBOV virus-like particles (VLPs) as well as infectivity of GP1,2-pseudotyped viruses. We further show that this effect is mediated through two mechanisms. First, high levels of GP1,2 expression reduce synthesis of other proteins needed for virus assembly. Second, viruses containing high levels of GP1,2 are intrinsically less infectious, possibly due to impaired receptor binding or endosomal processing. Importantly, proteolysis can rescue the infectivity of high-GP1,2-containing viruses. Taken together, our findings indicate that GP1,2 expression levels have a profound effect on factors that contribute to virus fitness and that RNA editing may be an important mechanism employed by EBOV to regulate GP1,2 expression in order to optimize virus production and infectivity.


OBJECTIVE
The Ebola virus (EBOV), as well as other members of the Filoviridae family, causes severe hemorrhagic fever that is highly lethal, with up to 90% mortality. The EBOV surface glycoprotein (GP1,2) plays important roles in virus infection and pathogenesis, and its expression is tightly regulated by an RNA-editing mechanism during virus replication. Our study demonstrates that the level of GP1,2 expression profoundly affects virus particle production and release and uncovers a new mechanism by which Ebola virus infectivity is regulated by the level of GP1,2 expression. These findings extend our understanding of EBOV infection and replication in adaptation of host environments, which will aid the development of countermeasures against EBOV infection.
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Gopi S
GS
Mohan
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Ling
L
Ye
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Wenfang
W
Li
Department of Pathology, Emory University, Atlanta, Georgia, USA.
Ana
A
Monteiro
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Xiaoqian
X
Lin
Department of Dermatology, Emory University, Atlanta, Georgia, USA.
Bishu
B
Sapkota
Department of Veterans' Affairs, Atlanta VA Medical Center, Decatur, Georgia, USA Department of Dermatology, Emory University, Atlanta, Georgia, USA.
Brian P
BP
Pollack
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA rcompan@emory.edu chyang@emory.edu.
Richard W
RW
Compans
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA rcompan@emory.edu chyang@emory.edu.
Chinglai
C
Yang
D002460:Cell Line; D029043:Ebolavirus / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D017393:RNA Editing; D053586:Virus Internalization; D057074:Virus Release; D014779:Virus Replication
D008562:Membrane Glycoproteins