Modulation of Paracellular Permeability in SARS-CoV-2 Blood-to-Brain Transcytosis

Area of Science:

• Neuroscience
• Virology
• Cell Biology

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects multiple organs, including the brain, but the mechanism of blood-brain barrier (BBB) traversal is not fully understood.
• The roles of angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4) in SARS-CoV-2 brain entry require further investigation.

Purpose of the Study:

• To investigate the mechanisms by which SARS-CoV-2 crosses the BBB.
• To determine the involvement of ACE2 and DPP4 receptors in SARS-CoV-2 infection of BBB cellular components.
• To assess the impact of direct SARS-CoV-2 infection on BBB permeability.

Main Methods:

• Utilized a transwell BBB model composed of human umbilical vein endothelial cells (HUVECs), astrocytes, and pericytes.
• Investigated SARS-CoV-2 interaction with ACE2 and DPP4 receptors on BBB cellular components.
• Analyzed viral entry pathways, including clathrin- and caveolin-mediated endocytosis.
• Assessed changes in paracellular permeability of the BBB model post-infection.

Main Results:

• Direct SARS-CoV-2 infection of the BBB model did not alter paracellular permeability.
• SARS-CoV-2 utilizes clathrin- and caveolin-mediated endocytosis to cross the BBB.
• Viral entry resulted in infection of the brain side of the BBB model with minimal endothelial cell infection.
• Both ACE2 and DPP4 receptors are implicated in the infection of endothelial cells, astrocytes, and pericytes.

Conclusions:

• The BBB is vulnerable to SARS-CoV-2 infection through direct cellular infection and transcytosis.
• SARS-CoV-2 can infect endothelial cells, astrocytes, and pericytes of the BBB via ACE2 and/or DPP4.
• Blood-to-brain transcytosis of SARS-CoV-2 can occur independently of host cell receptors.