SARS-CoV and MERS-CoV, two other betacoronaviruses, bear a striking resemblance to SARS-CoV-2, therefore studies done on neural infection in these alternate betacoronaviruses may help us glean insight on the neuroinvasive potential of SARS-CoV-2. Even though the expression level of ACE2 receptors (likely responsible for mediating the entry of both SARS-CoV and SARS-CoV-2) in the CNS is very low under normal conditions, SARS-CoV has been found in the neurons of the CNS. It is unclear exactly how betcoronaviruses can enter the neurons in CNS, but some hypotheses include entry via either the hematogenous or lymphatic route or via the PNS. Another betacoronavirus, avian bronchitis virus, infects the brainstem. The areas of the brainstem that it infects includes the solitary tract, which receives sensory input from the lungs and respiratory tract, and the nucleus ambiguus, which, along with the solitary tract, innervates airways smooth muscle, gland, and blood vessels. Infection in these areas that serve the overall purpose of the cardiorespiratory centre in the brainstem is the typical cause of death in infected animals. Our knowledge about SARS-CoV-2 can be expanded by understanding other betacoronaviruses, especially SARS-CoV and MERS-CoV.

The Neuroinvasive Potential of SARS-CoV-2

ACE2 is a surface bound enzyme, but when mice neuro-2A cells were exposed to Ang II and AT1R was activated, ACE2 was removed from the surface of the cell and degraded by lysosomes.  This may be a relevant mechanism related to SARS-CoV-2 cell entry.  

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Ang II is the produce of Ang I being cleaved by ACE.  This molecule is considered biologically active because it can influence physiological outcomes by acting on either Ang II type 1 receptors (AT1R) or Ang type 2 (AT2R) receptors.  

Angiotensin II (Ang II)

When activated by Ang II, this receptor results in the following physiological outcomes:

- vasoconstriction

- inflammation

- reabsorption of salts and water

- oxidative stress, accelerated aging and brain degeneration

- kidney failure

- heart disease

- apoptosis


Ang II type 1 receptors (AT1R)

- Neuronal ACE2 Expression as a Risk Factor for COVID-19
- Neuronal ACE2 Internalization in COVID-19
- ACE2 Expression in BBB
- ACE2 Expression in neuroglial cells
- ACE2 Expression in the ENS and Choroid Plexas

ACE2 and its Implications in SARS-CoV2 infection of the CNS

Xu, J., & Lazartigues, E. (2020). Expression of ACE2 in Human Neurons Supports the Neuro-Invasive Potential of COVID-19 Virus. Cellular and Molecular Neurobiology, 1-5.
https://link.springer.com/article/10.1007/s10571-020-00915-1

Expression of ACE2 in Human Neurons Supports the Neuro-Invasive Potential of COVID-19 Virus

A receptor that is activated by Ang II.  

Ang II type 2 receptors (AT2R)

Neuronal ACE2 Internalization in COVID-19

ACE2 is a homologue of ACE.  Both enzymes are carboxypeptidases, meaning they cleave amino acids from the c-terminal of the peptide.  However, these homologues cleave the amino acid sequences at different points which leads to their different products.  ACE2 has four main physiological roles:

- Regulating blood pressure via its role in the renin-angiotensin-aldosterone system (RAAS)

- Limiting the amount of ACE substrate by converting Ang I into Ang 1-9

- Degrading Ang II in order to minimize its harmful effects

- Forming Ang 1-7 in order to maximize its cardioprotective effects

Angiotensin-converting enzyme 2 (ACE2)

ACE2 was found to be heavily expressed in the cell body of artificial, stem cell derived neurons, and less so in the axons and dendrites. Data from human brain tissue is yet to be collected, but these findings as well as other studies using mice brain tissue suggest that ACE2 expression in neurons could make them susceptible to SARS-CoV-2 infection.  

Neuronal ACE2 Expression as a Risk Factor for COVID-19

- Investigate the density of the expression levels of ACE2 in the CNS
- Mechanism of the infection at molecular level
- Figures included

SARS-CoV-2 virus exploits the ACE2 receptor to gain entry into the cells

- SARS-CoV-2 may directly infect neurons via ACE2 protein on the surface of neurons. 
- Cytokines secreted from infected neurons damage nearby neurons and glial cells 


SARS-CoV-2 may directly infect neurons via ACE2 protein: possible mechanisms in figure

- SARS-CoV-2 may enter the blood vessels through mucosa and infected lungs: binds to ACE2 expressed in endothelial cells, disrupting the blood-brain barrier. - This may cause cerebral edema and intracranial hypertension. 


SARS-CoV-2 may enter BBB and affect CNS

- The ACE2 is expressed in both neurons and glia, particularly present in the brain stem and in the regions responsible for cardiovascular regulation
- SARS-CoV-1 was found in cerebrum not cerebellum may because by the distinct ratios between neurons and neuroglia(cerebrum has more glia cells)
- SARS-CoV-2 could  infect brain regions by triggering reactive astrogliosis and activation of microglia which leads to Neuroinflammation.
- Neuroinflammation together with prolonged hypoxia may promote neuropsychiatric developments and cognitive impairments both acute and chronic.

SARS-CoV-2 may infect CNS by targeting neuroglial cells  


- Histological Evidence for the Enteric Nervous System and the Choroid Plexus as Alternative Routes of Neuroinvasion by SARS-CoV2

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