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Review
. 2021 Mar 6;22(5):2681.
doi: 10.3390/ijms22052681.

Interactions of SARS-CoV-2 with the Blood-Brain Barrier

Michelle A Erickson  1   2 , Elizabeth M Rhea  1   2 , Rachel C Knopp  1   2 , William A Banks  1   2
Affiliations
Review

Interactions of SARS-CoV-2 with the Blood-Brain Barrier

Michelle A Erickson et al. Int J Mol Sci. .

Abstract

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood-brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.

Keywords: APOE; COVID-19; SARS-CoV-2; blood–brain barrier; brain; hypoxia; inflammation; thrombosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Impact of SARS-CoV-2 on the BBB structure and function. (i) Model of the neurovascular unit showing brain endothelial cells, pericytes, and astrocytes. (ii) Model of SARS-CoV-2 virion structure. (iii) Proposed direct effects of SARS-CoV-2 on the BBB. (A) BBB disruption that occurs due to SARS-CoV-2 protein interactions with the brain endothelial cell can cause non-specific leakage of serum factors into the brain. (B) SARS-CoV-2 protein interactions with brain endothelial cells may cause the release of cytokines, proteases, or clotting factors into the blood or brain compartments, as well as (C) increased expression of cell adhesion molecules which could contribute to leukocyte trafficking. (iv) Proposed indirect effects of SARS-CoV-2 on the BBB. (D) SARS-CoV-2 infection can increase circulating concentrations of pro-inflammatory cytokines and clotting factors, and decrease oxygen levels which may induce (E) BBB disruption via paracellular or transcellular routes, (F) increased production and release of cytokines and proteases by the brain endothelium, and (G) upregulation of brain endothelial cell adhesion molecules and leukocyte trafficking to the brain.
Figure 2
Figure 2
Mechanisms of SARS-CoV-2 entry into the brain across brain endothelial cells. The left panel (A–E) shows proposed mechanisms of entry via (A) ACE-2-dependent infection and replication inside brain endothelial cells, resulting in viral release on the brain side, (B) ACE2-dependent transport across the endothelial cell without replication, (C) receptor-mediated transport by a receptor other than ACE2, (D) transport mediated by adsorptive transcytosis, (E) transport that is mediated through interactions with the endothelial glycocalyx. The right panel (F–J) shows mechanisms by which inflammation or other pathological conditions may enhance or additionally contribute to SARS-CoV-2 brain entry. Inflammation can increase brain endothelial vesicular pathways of leakage (F), or formation of transendothelial channels (G) which may be large enough to permit viral leakage from blood. Inflammation and other diseases may contribute to upregulation of ACE2 (H) or other receptors that could increase viral infection and/or transport. Reduction or change in composition of the brain endothelial glycocalyx (I) could alter the interactions of SARS-CoV-2 with the endothelium. Finally, trafficking of immune cells across the BBB may be upregulated during inflammation or other pathological conditions (J), which could facilitate viral entry via a Trojan horse mechanism if the immune cell is infected.
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