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 

The points below list major concerns surrounding speculation of SARS-CoV-2 neuroinvasion:
- Assessing the ability for SARS-CoV-2 to infect human neurons (in the bulb or elsewhere) will ultimately require detailed analysis of autopsy tissue, studies of which do not yet exist.
- Many of the observed neurological consequences of COVID-19 (like altered consciousness and stroke) can in principle be explained by a primary asculopathy and hypercoagulability or by a secondary deficit in brain perfusion caused by elevated cytokines, rather than by direct viral damage


Controversy: Is SARS-CoV-2 ‘‘Neuroinvasive’’? 


- Hypothesized Mechanisms for SARS-CoV-2 Direct Invasion of the CNS
- Controversy: Is SARS-CoV-2 "Neuroinvasive"?

Smith College

COVID-19 patients have shown symptoms of direct and indirect neurological effects, from changes in taste and smell, to immunologic factors in cerebral spinal fluid (CSF).  It is unknown whether these phenomena are the result of neurological damage, of SARS-CoV-2 infection, and/or of indirect effects of the immune response. Furthermore, studies in mice have shown that neurons are susceptible to infection, suggesting that cells of the CNS may contribute to the deteriorating breathing and respiratory function of COVID-19 patients. The image below is an early hypothesized mechanism of viral entry through nasal and oral mucosa cells, though there is not yet any evidence to support this hypothesis.

Effects of COVID-19 on the Central Nervous System

Many of the known coronaviruses are neurotropic, meaning they are able to infect neuron cells.  If these observed trends carry over to SARS-CoV-2, they could help to elucidate how the CNS is affected by COVID-19.  Some of the key observations include:

- human coronavirus OC43 was shown to transmit itself to different neurons via axons in mice
- neuronal ACE2 expression in mice was found to be in different pre-autonomic regions of the brain which could explain why infected COVID-19 patients with dangerously low blood oxygen levels don't gasp for air
- SARS-CoV was found to infect regions of the brain that deal with cardiopulmonary regulation in human ACE2 knock-in mice
- SARS-CoV patient autopsies showed that the virus affected neurons more than any other kind of cell

Trends in Other Coronaviruses Affecting the CNS
 Relevant to COVID-19

- 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

- Autoimmune Response Contribution to Neurological Symptoms.
- Neuro-Immune Cellular Interactions from SARS-CoV-2 Infection.

Indirect/Downstream effects of SARS-CoV-2 on the CNS.

Even in the absence of typical respiratory symptoms such as fever, cough, and shortness of breath, various patients diagnosed with COVID-19 have presented neurological symptoms, such as:

- acute cerebrovascular diseases

- impaired consciousness

-  skeletal muscle injury

- encephalopathy (symptoms: ischemic stroke)

- loss of smell (anosmia) and taste (ageusia)

- stroke

- cranial nerve deficits

- delirium

- meningitis

- paralysis

- seizures

- neuroinflammatory syndromes

- high pressure CSF

- muscle stiffness

The list below includes less-common neurological symptoms of COVID-19:
- Guillain–Barré syndrome (GBS)
- Multisystem Inflammatory Syndrome in Children (MIS-C)

Neurological symptoms Presented in COVID-19 Patients

- Brain degeneration

- Cognitive decline

- Mental disorders


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