The goal was to determine whether SARS-CoV-2 can enter the brain via enteric neurons and pass through the gut brain axis, into the brain. 

Methods: 
- They immunostained ACE2 and TMPRSS2, two proteinases that cause SARS-CoV-2 to enter cells, in the area between the nervous system and non-nervous system organs, in the small and large intestine, choroid plexus, and the brain parenchyma.
- They collected tissue samples from patients who had been operated on and cadavers.

Results:
- The ACE2 and TMPRSS2 were found in layers in the intestinal wall and ENS. 
- TMPRSS2 was found in the cytoplasm of enteric epithelial cells. 
- ACE2 was found in the enteric neurons and glial cells, but not in the dendrites or axons of enteric neurons
- ACE2 and TMPRSS2 were both strongly found in the choroid plexus, but were weakly found in the brain parenchyma
- The results support the hypothesis that SARS-CoV-2 can enter the brain via enteric neurons, as these cells do express ACE2 and TMPRSS2 
- Further, ACE2 and TMPRSS2 were found in the glial cells of the ENS, which infection of these cells might harm the immune response, which may contribute to the cytokine storm. 
- Further, ACE2 and TMPRSS2 were found in the glial cells of the ENS, which infection of these cells might harm the immune response, which may contribute to the cytokine storm. 
- That ACE2 and TMPRSS2 were found in the choroid plexus suggests a possible route through the choroid plexus, through the CFS, and one through the fenestrated blood vessels. 
- The weak stainings of the brain parenchyma reject the hypothesis that the virus enters the brain through the blood brain barrier.
- The entry through the olfactory neurons is also unlikely because the olfactory receptor neurons did not express ACE2, only the sustentacular cells. 


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

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

Georgetown University

- 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

Deffner F, Scharr M, Klingenstein S, Klingenstein M, Milazzo A, Scherer S, Wagner A, Hirt B, Mack AF, Neckel PH. Histological Evidence for the Enteric Nervous System and the Choroid Plexus as Alternative Routes of Neuroinvasion by SARS-CoV2. Front Neuroanat. 2020 Oct 6;14:596439. doi: 10.3389/fnana.2020.596439. PMID: 33122999; PMCID: PMC7573115.

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

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

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.  

Neuronal ACE2 Internalization in 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.

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