Neurological Complications Associated with the Blood-Brain Barrier Damage Induced by the Inflammatory Response During SARS-CoV-2 Infection

Abstract

The main discussion above of the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has focused substantially on the immediate risks and impact on the respiratory system; however, the effects induced to the central nervous system are currently unknown. Some authors have suggested that SARS-CoV-2 infection can dramatically affect brain function and exacerbate neurodegenerative diseases in patients, but the mechanisms have not been entirely described. In this review, we gather information from past and actual studies on coronaviruses that informed neurological dysfunction and brain damage. Then, we analyzed and described the possible mechanisms causative of brain injury after SARS-CoV-2 infection. We proposed that potential routes of SARS-CoV-2 neuro-invasion are determinant factors in the process. We considered that the hematogenous route of infection can directly affect the brain microvascular endothelium cells that integrate the blood-brain barrier and be fundamental in initiation of brain damage. Additionally, activation of the inflammatory response against the infection represents a critical step on injury induction of the brain tissue. Consequently, the virus' ability to infect brain cells and induce the inflammatory response can promote or increase the risk to acquire central nervous system diseases. Here, we contribute to the understanding of the neurological conditions found in patients with SARS-CoV-2 infection and its association with the blood-brain barrier integrity.

Keywords: Blood-brain barrier; COVID-19; Inflammatory response; Neurological complications; Neurotropism; SARS-CoV-2.

Fig. 1

SARS-CoV-2 genome organization. The SARS-CoV-2 genome size is around 32 kb and is an RNA single-strand positive-sense that encodes 16 non-structural proteins (5′ end) and 4 structural proteins (3′ end) (S, E, M, and N) and 6 accessory proteins. SARS-CoV-2 genome. The genome contains a PoliA tail at 3′ end

Fig. 2

Possible mechanism of damage to the blood-brain barrier (BBB) by the action of SARS-CoV-2. a Expression of angiotensin-converting enzyme 2 (ACE2) and the pro-protein convertase furin (PCF) in the membrane of the brain microvascular endothelial cells facilitates SARS-CoV-2 infection. b SARS-CoV2 infection activates the brain microendothelial cells inducing high expression of the vascular and the intercellular adhesion molecules (VCAM and ICAM). Likewise, SARS-CoV-2 induces the expression and activation matrix metalloproteinases (MMP) that degrade tight junctions proteins. c Recognition of ICAM and ICAM through the β1 and β2 integrins causes binding of circulating leukocytes to endothelial cells that lead transcellular extravasation. This process facilitate viral entrance to the cerebral parenchyma through the “Trojan horse” mechanism. d SARS-CoV-2 viral replication induces endothelial cell contraction and lysis. Increased permeability of the BBB allows extravasation of plasma proteins and blood cells. Activation of leukocytes and platelets contributes to the BBB damage. Besides, endothelial cell death disturbs the microenvironment of the brain parenchyma allowing free passage of the SARS-CoV-2 virus and infection of other cells of the central nervous system