Hypothesis:

- SARS-CoV2 infection of immune-cells and the subsequent upregulation of cytokines and chemokines may interact with lung-innervating sensory neurons, providing a neurological model for COVID-19 severity.

The image below shows a proposed mechanism of the neuro-immune interactome; SARS-CoV-2 activation of the immune cell results in an inflammatory cytokine storm, along with the upregulation of COVID-19 inflammatory ligands that bind to sensory neurons receptors; neurologic inflammation may occur following the release of neuropeptides, forming a positive-feedback loop that could exacerbate lung inflammation (Ray et. al).

Neuro-Immune Cellular Interactions from SARS-CoV-2 Infection.

Support for indirect over direct causes of neurological symptoms:
- Cerebralspinal fluid (CSF) samples in some CoV-2 patients have shown the presence of SARS-CoV-2 antibodies (anti-S1 IgM) and increased multiple cytokines, suggesting a possible CoV-2 direct infection of the CNS (Benameur et. al). However, this coupled with low levels of CSF and plasma viral RNA in patients, suggests that the neurological symptoms present may be a result of autoimmune responses, rather than direct infection.

Support for autoimmunity:
- the anti-neuronal and anti-glial autoantibodies presence in CSF and serum lends support of a causal relationship between autoimmunity and neurological clinical symptoms (Franke et. al)
- transcriptomic data from COVID-19 patients, control samples, and mice studies, reveal evidence of virus-driven cell lysis (Ray et. al)

COVID-19 Neurological Effects as a Result of Autoimmunity in the PNS

- Direct infection injury detected in tissue samples 
- Blood circulation pathway, entering the CNS through BBB
- Neuronal pathway (e.g. olfactory neuron transport) infecting sensory or motor nerve endings
- Hypoxia injury, damages caused by lack of oxygen circulation
- Immune injury-- systemic inflammatory response syndrome(SIRS)
- Affecting the ability of ACE2 enzyme to regulate blood pressure, damaging the BBB

Mechanisms of CoV infections on the nervous system damage

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

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

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


Expected Long-Term Outcomes of Acute SARS-Cov2 Infection on CNS

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

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