SARS-CoV-2 Spike Protein Disrupts Blood–Brain Barrier Integrity via RhoA Activation

Abstract

Graphic Abstract The SARS-CoV-2 spike protein has been shown to disrupt blood–brain barrier (BBB) function, but its pathogenic mechanism of action is unknown. Whether angiotensin converting enzyme 2 (ACE2), the viral binding site for SARS-CoV-2, contributes to the spike protein-induced barrier disruption also remains unclear. Here, a 3D-BBB microfluidic model was used to interrogate mechanisms by which the spike protein may facilitate barrier dysfunction. The spike protein upregulated the expression of ACE2 in response to laminar shear stress. Moreover, interrogating the role of ACE2 showed that knock-down affected endothelial barrier properties. These results identify a possible role of ACE2 in barrier homeostasis. Analysis of RhoA, a key molecule in regulating endothelial cytoskeleton and tight junction complex dynamics, reveals that the spike protein triggers RhoA activation. Inhibition of RhoA with C3 transferase rescues its effect on tight junction disassembly. Overall, these results indicate a possible means by which the engagement of SARS-CoV-2 with ACE2 facilitates disruption of the BBB via RhoA activation. Understanding how SARS-CoV-2 dysregulates the BBB may lead to strategies to prevent the neurological deficits seen in COVID-19 patients. Supplementary Information The online version contains supplementary material available at 10.1007/s11481-021-10029-0.

Penetration of the SARS-CoV-2 Spike Protein across the Blood–Brain Barrier, as Revealed by a Combination of a Human Cell Culture Model System and Optical Biosensing

“…Here we investigated the passage of the SARS-CoV-2 spike protein S1 subunit across a human brain endothelial cell-based culture BBB model for the first time. Previously it was shown that spike protein treatment alters barrier integrity and induces the activation of endothelial cells [ 29 , 30 ]. During our investigation short-term spike protein S1 subunit treatment did not change the resistance of the BBB model.…”

Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology

“…Indeed, upon SARS-CoV-2 infection, the expression of MMP9 increases, while the expression of collagen IV decreases [122]. Additionally, the spike protein of SARS-CoV-2 disrupts the BBB integrity via RhoA activation [123]. SARS-CoV-2 was suggested to damage the choroid plexus epithelium, which led to the leakage of the blood-CSF barrier in human brain organoids [124].…”

The Neuroimmune Pharmacology of SARS-CoV-2

“…Dr. Galie’s lab has established a compliant 3D blood–brain barrier (BBB) microfluidic model. Based on the following two premises, 1) SARS-CoV-2 spike protein disrupts blood–brain barrier (BBB); 2) It is not known if angiotensin converting enzyme 2 (ACE2), the binding site for SARS-CoV-2, is involved in BBB disruption, the lab studied molecular and cellular mechanisms underlying disruption of BBB by SARS-CoV-2 spike protein using their 3D-BBB model (DeOre et al 2021 ). Their studies demonstrated: 1) The expression of ACE2 was increased in response to laminar shear stress; 2) Knock down of ACE2 affected the BBB properties; 3) Spike protein triggered activation of RhoA, a key protein in regulating endothelial cytoskeleton and tight junction complex dynamics, leading to the change of BBB properties; 4) Inhibition of activation of RhoA by C3 transferase reversed the spike protein’s effects.…”

“…First, we present, “The COVID-19 pandemic: Reflections of science, person, and challenge in academic research settings,” which collects various perspectives from the Society’s spring 2021 virtual workshop symposium focused on well-being and reflections (Bidlack et al 2021 ). Then, there are two brief reports: “Cannabis/Cannabinoids for Treating COVID-19 Associated Neuropsychiatric Complications” (Khalsa et al 2021 ) and “SARS-CoV-2 spike protein disrupts blood–brain barrier integrity via RhoA activation” (DeOre et al 2021 ). Next comes the issue’s review paper, “Racial Health Disparity and COVID-19” (Kumar et al 2021b ) followed by three original research articles.…”