-The highest levels of viral RNA and S proteins for SARS-CoV-2 were found within the olfactory mucosa sampled directly beneath the cribriform plate, as compared to other regionally defined tissue samples, indicating the area as an entry point. 

-Proximity of neurons, nerve fibers and mucosa within the oro- and nasopharynx and the reported clinical–neurological signs related to altered smell and taste perception suggest that the neural–mucosal interface is exploited as a port of entry into the CNS. 

-Local CNS infection was identified by HLA-DR+ inflammatory response in the CSF, with increased levels of inflammatory mediators such as interleukin (IL)-6.

Figure: Various SARS-CoV-related investigations of the individuals who tested positive for SARS-CoV-2 by RT–qPCR in the olfactory mucosa (OM), the CNS or both. SARS-CoV-2 RT–qPCR positivity was combined with results derived from SARS-CoV-specific immunohistochemistry (IHC) and ISH as well as EM in appropriate tissue as available.

Cellular mucosal–nervous micromilieu analysis and  regional mapping of olfactory nervous tracts and defined CNS regions in autopsy material 

SARS-CoV-2 RNA and spike (S) protein have been detected in both the olfactory mucosa and the CNS of COVID-19 patients, with the highest viral loads reported in the olfactory mucosa beneath the cribriform plate. These findings support the hypothesis that the virus exploits the neural–mucosal interface of the olfactory region as a port of entry into the CNS.

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1. Entry through the naval cavity: because intranasal drug delivery bypasses the blood brain barrier to delivery therapeutic agents directly to the CNS, it is thought that SARS-CoV-2 can likewise infect the brain via olfactory nerves.
  
2. Entry through the lungs: previous speculation that SARS-CoV could infect the , brainstem via chemoreceptors and mechanoreceptors in the respiratory system lend possibility for a neurotropic mechanism for SARS-CoV-2.

These hypotheses have yet to be validated.  
Figure below shows coronavirus infection mechanisms (Wu et. al).

Hypothesized Mechanisms for SARS-CoV-2 Direct Invasion of the CNS 

- K18-hACE2 mice brain tissue shows no viral infection in olfactory tissue

Reports Supporting SARS-CoV-2 Direct CNS Invasion Through the Lungs

- Increasing data suggest that ACE2 is not appreciably expressed in neurons in the brain at either the RNA or protein level. 
- scSeq analysis of human prefrontal cortex and hippocampus failed to identify any ACE2- expressing cells 
- multiple immunostaining studies have demonstrated ACE2 expression in brain vasculature but not in neurons or glia 


Support Against SARS-CoV-2 Direct Invasion of Neurons and Glial Cells

- Potential neuroinvasive pathways of SARS-CoV-2: Deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19)
- SARS-CoV-2 entry through the blood brain barrier (BBB)

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