Ebola virus glycoprotein toxicity is mediated by a dynamin-dependent protein-trafficking pathway.
Ebola virus infection causes a highly lethal hemorrhagic fever syndrome associated with profound immunosuppression through its ability to induce widespread inflammation and cellular damage. Though GP, the viral envelope glycoprotein, mediates many of these effects, the molecular events that underlie Ebola virus cytopathicity are poorly understood. Here, we define a cellular mechanism responsible for Ebola virus GP cytotoxicity. GP selectively decreased the expression of cell surface molecules that are essential for cell adhesion and immune function. GP dramatically reduced levels of alphaVbeta3 without affecting the levels of alpha2beta1 or cadherin, leading to cell detachment and death. This effect was inhibited in vitro and in vivo by brefeldin A and was dependent on dynamin, the GTPase. GP also decreased cell surface expression of major histocompatibility complex class I molecules, which alters recognition by immune cells, and this effect was also dependent on the mucin domain previously implicated in GP cytotoxicity. By altering the trafficking of select cellular proteins, Ebola virus GP inflicts cell damage and may facilitate immune escape by the virus.
Sullivan
Nancy J
NJ
Vaccine Research Center, National Institute for Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20814, USA.
Peterson
Mary
M
Yang
Zhi-yong
ZY
Kong
Wing-pui
WP
Duckers
Heinricus
H
Nabel
Elizabeth
E
Nabel
Gary J
GJ
D000818:Animals; D002339:Carotid Arteries; D015536:Down-Regulation; D034281:Dynamins / Q000378:metabolism*; D029043:Ebolavirus / Q000378:metabolism / Q000472:pathogenicity*; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D009077:Mucins / Q000378:metabolism; D013552:Swine; D014162:Transfection; D014759:Viral Envelope Proteins / Q000378:metabolism / Q000633:toxicity*
D015395:Histocompatibility Antigens Class I; D039302:Integrin alphaVbeta3; D009077:Mucins; D014759:Viral Envelope Proteins; C113189:envelope glycoprotein, Ebola virus; D034281:Dynamins