Recombinant ACE2 Expression Is Required for SARS-CoV-2 To Infect Primary Human Endothelial Cells and Induce...

Area of Science:

• Virology
• Cell Biology
• Pathogenesis

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease characterized by acute respiratory distress syndrome (ARDS), inflammation, and coagulopathy.
• The role of endothelial cells (ECs) in SARS-CoV-2 pathogenesis is debated, with theories suggesting direct infection via angiotensin-converting enzyme 2 (ACE2) receptors.

Purpose of the Study:

• To investigate whether SARS-CoV-2 directly infects human endothelial cells (ECs).
• To elucidate the mechanism by which SARS-CoV-2 impacts EC function in the context of COVID-19.

Main Methods:

• Primary human ECs from various tissues were assessed for ACE2 receptor expression.
• ECs were transduced with recombinant ACE2 and subsequently infected with SARS-CoV-2.
• Viral replication, syncytia formation, cell lysis, and procoagulative/inflammatory responses were analyzed.

Main Results:

• Primary human ECs from lung, kidney, heart, brain, and umbilical veins lack detectable ACE2 receptors and are not infected by SARS-CoV-2.
• ECs engineered to express ACE2 receptors were susceptible to SARS-CoV-2 infection, leading to high viral titers, syncytia, and lysis.
• Infection of ACE2-expressing ECs induced procoagulative and inflammatory responses mirroring those seen in COVID-19 patients.

Conclusions:

• The endothelium is not a primary target for direct SARS-CoV-2 infection due to the absence of ACE2 receptors on ECs.
• SARS-CoV-2 likely indirectly activates ECs, contributing to thrombosis and endotheliitis observed in COVID-19.
• Therapeutic strategies should focus on epithelial responses or potential ACE2-independent EC infection pathways.