Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus

Jia Chen, Karthik Sathiyamoorthy, Xianming Zhang, Samantha Schaller, Bethany Elena Perez-White, Theodore S. Jardetzky, Richard M Longnecker*

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Epstein-Barr virus (EBV) is an oncogenic virus that infects more than 90% of the world's population 1 . EBV predominantly infects human B cells and epithelial cells, which is initiated by fusion of the viral envelope with a host cellular membrane 2 . The mechanism of EBV entry into B cells has been well characterized 3 . However, the mechanism for epithelial cell entry remains elusive. Here, we show that the integrins αvβ5, αvβ6 and αvβ8 do not function as entry and fusion receptors for epithelial cells, whereas Ephrin receptor tyrosine kinase A2 (EphA2) functions well for both. EphA2 overexpression significantly increased EBV infection of HEK293 cells. Using a virus-free cell-cell fusion assay, we found that EphA2 dramatically promoted EBV but not herpes simplex virus (HSV) fusion with HEK293 cells. EphA2 silencing using small hairpin RNA (shRNA) or knockout by CRISPR-Cas9 blocked fusion with epithelial cells. This inhibitory effect was rescued by the expression of EphA2. Antibody against EphA2 blocked epithelial cell infection. Using label-free surface plasmon resonance binding studies, we confirmed that EphA2 but not EphA4 specifically bound to EBV gHgL and this interaction is through the EphA2 extracellular domain (ECD). The discovery of EphA2 as an EBV epithelial cell receptor has important implications for EBV pathogenesis and may uncover new potential targets that can be used for the development of novel intervention strategies.

Original languageEnglish (US)
Pages (from-to)172-180
Number of pages9
JournalNature Microbiology
Volume3
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Ephrin-A2
Complement 3d Receptors
Eph Family Receptors
Human Herpesvirus 4
Epithelial Cells
HEK293 Cells
EphA2 Receptor
B-Lymphocytes
Clustered Regularly Interspaced Short Palindromic Repeats
Virus Internalization
Oncogenic Viruses
Epstein-Barr Virus Infections
Surface Plasmon Resonance
Cell Fusion
Simplexvirus
varespladib methyl
Integrins
Small Interfering RNA
Viruses

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Chen, Jia ; Sathiyamoorthy, Karthik ; Zhang, Xianming ; Schaller, Samantha ; Perez-White, Bethany Elena ; Jardetzky, Theodore S. ; Longnecker, Richard M. / Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. In: Nature Microbiology. 2018 ; Vol. 3, No. 2. pp. 172-180.
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Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. / Chen, Jia; Sathiyamoorthy, Karthik; Zhang, Xianming; Schaller, Samantha; Perez-White, Bethany Elena; Jardetzky, Theodore S.; Longnecker, Richard M.

In: Nature Microbiology, Vol. 3, No. 2, 01.02.2018, p. 172-180.

Research output: Contribution to journalArticle

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