Epstein-Barr Virus Lytic Replication Induces ACE2 Expression and Enhances SARS-CoV-2 Pseudotyped Virus Entry in...

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into host cells is mediated by its spike protein binding to the ACE2 receptor.
• Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that can establish lifelong latency and reactivate.

Purpose of the Study:

• To investigate whether Epstein-Barr virus (EBV) influences the expression of Angiotensin-Converting Enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2.
• To determine if EBV replication enhances SARS-CoV-2 infectivity in epithelial cells.

Main Methods:

• Utilized vesicular stomatitis virus (VSV) pseudotyped with SARS-CoV-2 spike protein to assess viral entry.
• Employed promoter assays to examine the interaction between EBV's Zta protein and the ACE2 promoter.
• Infected oral keratinocytes with EBV to study ACE2 induction and SARS-CoV-2 pseudovirus entry.

Main Results:

• Epstein-Barr virus (EBV) induces ACE2 expression during its lytic replication cycle in epithelial cells.
• Lytic EBV replication significantly enhances ACE2-dependent entry of SARS-CoV-2 pseudoviruses.
• The EBV transcriptional activator Zta directly binds to and activates the ACE2 promoter, particularly when methylated.

Conclusions:

• Subclinical EBV replication and lytic gene expression in epithelial cells can increase susceptibility to SARS-CoV-2 infection by upregulating ACE2.
• These findings highlight a potential mechanism by which a common virus may exacerbate COVID-19.
• Antiviral therapies targeting EBV replication could be a strategy to reduce SARS-CoV-2 susceptibility.