- the loss of smell or taste is one of the first occurred COVID-19 symptoms

- SARS-CoV-2 like SARS-CoV and MERS-CoV could infect the nervous system through neurons in the nasal passage targeting olfactory bulb

- Experiment on transgenic mice expressing human ACE2 showed SARS-CoV enter CNS through neurons in the nose. 

- SARS-CoV-2 could work its way up to the olfactory mucosa, which consists of epithelium cells, blood vessels, and the axons from olfactory neurons, which lead to the frontal lobe.

- Loss of sense could be caused by inflammation as the body fights the virus

- SARS-CoV-2 infects medulla oblongata— part of the brain stem that serves as the control center for the heart and the lungs—causing acute respiratory failure for patients e.g. loss of involuntary breathing 

- SARS-CoV-2 cross BBB by circulating through the blood and then attack ACE2 receptors in the endothelia that lines blood capillaries in the brain, causing swelling and compression of brain stem


Lost smell and taste hint COVID-19 can target the nervous system

- 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  


Symptoms: 
- 54yr CoV-19 patient had anosmia and dysgeusia early, while seizures occurred as COVID-19 complication. 
- Two seizures starting from right frontotemporal region and diffusing in homologous contralateral hemisphere
- The delayed CNS damage appears mediated by the immune system 

Possible causes: 
- The pro-inflammatory state induced by the cytokine storm may be responsible of the activation of glial cells with subsequent demyelination 
- Alternative could be the production of antibodies against glial cells triggered by the virus, as a para-infective or post-infective phenomenon. 



SARS-CoV-2 can induce brain and spine demyelinating lesions


- Dr. Allen Aksamit Jr., a Mayo Clinic neurologist, discusses potential neurological effects of COVID-19
- Saying that there are overlaps in direct involvement of SARS-CoV-2 in nervous system and other systemic effects from respiratory or metabolic compromise
- The direct effects of the virus entering the nervous system are lacking proves in study; the neurological manifestations are more likely consequences of the disease's effect on the body

- Delirium can be a consequence of low oxygen to the brain— relatively infrequent 
- Mechanism of Stroke in CoV-19 patients is unclear; more related to pre-existing conditions that damage the blood vessels than direct involvement of SARS-CoV-2
- Muscle damage occurs as a consequence of infection in critical illness 
- Guillain-Barre syndrome caused by immune reaction against the nerves rather than direct effect of the virus


Mayo Clinic Q&A podcast: neurological manifestations — consequences of the effects of SARS-CoV-2 on the body


- 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

Smith College

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

- 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.

Wu, Y., Xu, X., Chen, Z., Duan, J., Hashimoto, K., Yang, L., ... & Yang, C. (2020). Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, behavior, and immunity. doi:10.1016/j.bbi.2020.03.031
https://www.sciencedirect.com/science/article/pii/S0889159120303573?via%3Dihub

Nervous system involvement after infection with COVID-19 and other coronaviruses.

Mechanisms of CoV infections on the nervous system damage

- Cerebrospinal fluid (CSF) (SARS/MERS)
- Olfactory bulb (SARS)
- Piriform and infra-limbic cortices (SARS)
- Ventral pallidum and lateral preoptic regions of the basal ganglia (SARS)
- Dorsal raphe (SARS)

Areas of the CNS Where Other CoV Antigens Have Been Detected

Patients who have recovered from SARS-Cov-1 demonstrate higher risks of developing Parkinson’s disease and multiple sclerosis. 31-50 months after the acute SARS-Cov-1 infection, Troyer et. al found evidence for post-traumatic stress disorder (39%), depression (36.4%), obsessive convulsive disorder (15.6%), and panic disorders (15.6%).


SARS-Cov-1 and Development of Neurodegenerative and Psychological Diseases

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)

Learn Before

Related

Learn After