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

Wakako Furuyama, Andrea Marzi, Aaron B. Carmody, Junki Maruyama, Makoto Kuroda, Hiroko Miyamoto, Asuka Nanbo, Rashid Manzoor, Reiko Yoshida, Manabu Igarashi, Heinz Feldmann, Ayato Takada

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Article numbere1006139
JournalPLoS pathogens
Volume12
Issue number12
DOIs
StatePublished - Dec 30 2016

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Furuyama, W., Marzi, A., Carmody, A. B., Maruyama, J., Kuroda, M., Miyamoto, H., Nanbo, A., Manzoor, R., Yoshida, R., Igarashi, M., Feldmann, H., & Takada, A. (2016). Fcγ-receptor IIa-mediated Src Signaling Pathway is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection. PLoS pathogens, 12(12), [e1006139]. https://doi.org/10.1371/journal.ppat.1006139