title: Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection.
abstract: Antibody-dependent enhancement (ADE) of Ebola virus (EBOV) infection has been demonstrated in vitro, raising concerns about the detrimental potential of some anti-EBOV antibodies. ADE has been described for many viruses and mostly depends on the cross-linking of virus-antibody complexes to cell surface Fc receptors, leading to enhanced infection. However, little is known about the molecular mechanisms underlying this phenomenon. Here we show that Fcγ-receptor IIa (FcγRIIa)-mediated intracellular signaling through Src family protein tyrosine kinases (PTKs) is required for ADE of EBOV infection. We found that deletion of the FcγRIIa cytoplasmic tail abolished EBOV ADE due to decreased virus uptake into cellular endosomes. Furthermore, EBOV ADE, but not non-ADE infection, was significantly reduced by inhibition of the Src family protein PTK pathway, which was also found to be important to promote phagocytosis/macropinocytosis for viral uptake into endosomes. We further confirmed a significant increase of the Src phosphorylation mediated by ADE. These data suggest that antibody-EBOV complexes bound to the cell surface FcγRIIa activate the Src signaling pathway that leads to enhanced viral entry into cells, providing a novel perspective for the general understanding of ADE of virus infection.
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Furuyama
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Marzi
authors.affiliation: Research Technologies Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, United States of America.
authors.forename: Aaron B
authors.identifier: http://orcid.org/0000-0003-4772-763X
authors.initials: AB
authors.lastname: Carmody
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
authors.forename: Junki
authors.initials: J
authors.lastname: Maruyama
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuroda
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Miyamoto
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Asuka
authors.identifier: http://orcid.org/0000-0001-8764-1350
authors.initials: A
authors.lastname: Nanbo
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
authors.forename: Rashid
authors.initials: R
authors.lastname: Manzoor
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Yoshida
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.|Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, United States of America.
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.|Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan.|School of Veterinary Medicine, the University of Zambia, Lusaka, Zambia.
authors.forename: Ayato
authors.initials: A
authors.lastname: Takada
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D019067:Antibody-Dependent Enhancement / Q000276:immunology*; D002522:Chlorocebus aethiops; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D017452:Receptors, IgG / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014709:Vero Cells; D053586:Virus Internalization; D019061:src-Family Kinases / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D019061:src-Family Kinases