Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection

PLoS Pathogens

Asuka Nanbo¹  Rashid Manzoor²  Makoto Kuroda²  Hiroko Miyamoto²  Manabu Igarashi²  Reiko Yoshida²  Wakako Furuyama²  Junki Maruyama²  Heinz Feldmann³  Andrea Marzi⁴  Ayato Takada⁴  Aaron B. Carmody⁵ 

[1] Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan;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;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;Research Technologies Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, United States of America

关键词: T cells;    Dengue virus;    Phosphorylation;    Vesicular stomatitis virus;    Signal inhibition;    Vesicles;    Lectins;    Membrane receptor signaling;   

DOI  :  10.1371/journal.ppat.1006139

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY