SARS-CoV-2: is there neuroinvasion?

Abstract

Background: SARS-CoV-2, a coronavirus (CoV), is known to cause acute respiratory distress syndrome, and a number of non-respiratory complications, particularly in older male patients with prior health conditions, such as obesity, diabetes and hypertension. These prior health conditions are associated with vascular dysfunction, and the CoV disease 2019 (COVID-19) complications include multiorgan failure and neurological problems. While the main route of entry into the body is inhalation, this virus has been found in many tissues, including the choroid plexus and meningeal vessels, and in neurons and CSF.

Main body: We reviewed SARS-CoV-2/COVID-19, ACE2 distribution and beneficial effects, the CNS vascular barriers, possible mechanisms by which the virus enters the brain, outlined prior health conditions (obesity, hypertension and diabetes), neurological COVID-19 manifestation and the aging cerebrovascualture. The overall aim is to provide the general reader with a breadth of information on this type of virus and the wide distribution of its main receptor so as to better understand the significance of neurological complications, uniqueness of the brain, and the pre-existing medical conditions that affect brain. The main issue is that there is no sound evidence for large flux of SARS-CoV-2 into brain, at present, compared to its invasion of the inhalation pathways.

Conclusions: While SARS-CoV-2 is detected in brains from severely infected patients, it is unclear on how it gets there. There is no sound evidence of SARS-CoV-2 flux into brain to significantly contribute to the overall outcomes once the respiratory system is invaded by the virus. The consensus, based on the normal route of infection and presence of SARS-CoV-2 in severely infected patients, is that the olfactory mucosa is a possible route into brain. Studies are needed to demonstrate flux of SARS-CoV-2 into brain, and its replication in the parenchyma to demonstrate neuroinvasion. It is possible that the neurological manifestations of COVID-19 are a consequence of mainly cardio-respiratory distress and multiorgan failure. Understanding potential SARS-CoV-2 neuroinvasion pathways could help to better define the non-respiratory neurological manifestation of COVID-19.

Keywords: ACE2; Aging; Blood–brain barrier (BBB); COVID-19; Cerebrospinal fluid (CSF); Choroid plexus; Diabetes; Hypertension; MMP9; Obesity.

Fig. 1

SARS-CoV-2 distribution in blood and possible entry into brain across the CNS vascular barriers. a Nasal entry. SARS-CoV-2 enters the nasal cavity as droplets, and (1) enters the airways with the inspired air, (2) traffic into the nasal sub mucosa via the highly vasculature of the nose and enters the blood and/or lymphatics and (3) may get access to the olfactory nerves and thus olfactory bulb by going upstream, but to date there is no sound data to viral entry into brain. b Vasculature entry. After it enters the lungs it may cross the thin alveolar membrane and enters the blood to access all organs, including brain, but there is no evidence that ACE2 mediate viral entery into brain. c Blood brain barrier (BBB). This is a highly specialized structure at the interface between the blood and the brain. It is formed by tight junctions at the endothelial cells and forms part of a complex cellular structure known as the neurovascular unit (NVU). The NVU is the functional unit of the BBB and is composed of multiple cells including, pericytes, astrocytes, microglia and neurons interacting with the endothelial cell, as well as the basement membrane, which all can affect the barrier properties. ACE2 is expressed both on endothelial cell and pericytes as well as some neurons in the brain, but there is no evidence that ACE2 mediate viral entery into brain. d Choroid plexus. This is at the interface between the blood and the CSF, known as the blood CSF barrier (BCSFB). The endothelial cells of the choroid plexus are leakier than in the BBB, with gaps known as fenestrations. This allows for easier movement from the blood, but the epithelium cells at the apical side are more tightly knitted together (tight junction at the apex of the epithelium), and prevent entry into CSF [261, 262], as effective as the cerebral capillaries. The choroid plexus epithelium expresses ACE2 and this acts as a possible way for SARS-CoV-2 entry into CSF and then brain parenchyma, but there is no sound evidence for this

Fig. 2

Renin-angiotensin system. ACE2 is exploited by SARS-CoV-2 when infecting host cells. Renin, secreted from the kidneys in response to changes in blood flow and pressure, catalyses the conversion of the plasma protein called angiotensinogen into angiotensin I, angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II acts via receptors in the adrenal gland, causing the secretion of aldosterone, which causes the kidney to reabsorb salt and water. Angiotensin II is a powerful vasoconstrictor. ACE2 activity alters the ratio between angiotensin I to angiotensin (1–9) and angiotensin II to angiotensin (1–7). Angiotensin (1–7) can be converted to angiotensin (1–9) by ACE, and both have been shown to cause vasodilation. It has been shown that SARS-CoV-2 spike protein binds to the ACE2 receptor and shift the balance towards angiotensin II

Fig. 3

Schematic diagram showing perivascular SARS-CoV-2 entry into brain. penetrating arterial vessel and a magnified region (boxed area) showing possible access site of the virus via the perivascular space. This could activate perivascular macrophage leading to neuroinflammation

Fig. 4

SARS-CoV-2 interaction and transport across the BBB. Normal and infected neurovascular unit (NVU). A normal BBB restricts and controls the entry of substances in and out of the brain. Tight junctions between endothelial cells restrict the movement via the paracellular route for small molecules, like ions (e.g., potassium, sodium). Along with this tight barrier there is also low levels of pinocytosis, numerous transporters for select molecules, and efflux pumps to remove substances from the brain into the blood. In an infected/diseased BBB, there is the possibilities that tight junctions loosen, allowing larger molecules to pass via the paracellular route into the brain, decrease in efflux pumps and transporters as well as increased pinocytosis altering the balance across the barrier. Basement membrane breakdown on the abluminal surface can cause increase the barrier permeability. Viral infection can cause the release of cytokines, which can alter the integrity of the BBB and increase immune cell penetration into the brain

Fig. 5

Prior health conditions effects on the BBB. Obesity is linked to increase in inflammatory cytokines which can lead to activation of astrocytes and microglia and death of neuronal cells, leading to wide spread neuro-inflammation, tight junction breakdown and damage to the CNS. Diabetes and hyperglycaemia cause pathological changes to the BBB, including increased capillary density, thickening of the basement membrane, breakdown of tight junctions and increase in paracellular diffusion. Pericytes are also shown to degenerate and aid in the decrease in barrier properties. Hypertension is linked to the RAS system and Ang-11 levels, increase in inflammatory cytokines and Reactive oxygen species (ROS) damage to endothelial cells and activation of microglia and astrocytes. Age has widespread effects on the BBB, decrease in barrier functions, decrease in efflux pumps and impaired energy utilization. There is also increased movement across the BBB by increase in paracellular movement, increase in pinocytosis leading to astrocytes and microglia activation

Fig. 6

Flow diagram showing possible effects of SARS-CoV-2 on the cerebrovasculature. CBF (cerebral blood flow), BBB (blood brain barrier), ACE2 (angiotensin converting enzyme 2), sACE2 (soluble ACE), IFN (interferon), CVS (cardiovascular centre), IL-1 (interleukin 1), TNFα (tumour necrosis factor α), CD147 (EMMPRIN (extracellular matrix metalloprotease inducer), ADAM17 (disintegrin and metalloprotease17), MMP9 (matrix metalloprotease 9), BP (blood pressure) and pO₂ (partial pressure of oxygen)