How SARS-CoV-2 enters the central nervous system

The central nervous system (CNS) is highly protected in the human body. Yet, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the CNS, causing profound clinical complications. How is the CNS involved in a respiratory virus infection?

To understand this, researchers Ruqaiyyah Siddiqui, Mohammad Ridwane Mungroo and Naveed Ahmed Khan reviewed reported case studies and identified potential brain regions that may be affected by the SARS-CoV-2 and explored the virus's possible entry route into the brain to identify its pathogenicity. In a recent review in the medical journal Hospital Practice, the team discussed the related clinical cases, symptoms, and targets.

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), the respiratory illness responsible for the COVID-19 pandemic. The novel virus belongs to the coronavirus family and has infected over 109 million people and claimed over 2.4 million lives since its emergence in late December 2019 in Wuhan, China. Coronaviruses are a family of ribonucleic acid viruses that are known to cause disease in humans and animals. SARS-CoV-2 is the seventh known coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV, and the original SARS-CoV-1

Clinicians and researchers from across the world strived to understand the SARS-CoV-2 infection. The most common symptoms are cough, fever, fatigue, and respiratory distress. Although it is predominantly a respiratory disease, neurological manifestations are also associated with it.

Evidence from other viruses

The predecessor of SARS-CoV-2, SARS-CoV-1, infects the brain. SARS-CoV-1 has been detected in neurons, causing focal degeneration and edema.

The MERS-CoV infects the CNS, with higher mortality rates as compared to lung infections. The neurological manifestations in these infections include delayed neurologic consequences, such as myopathy, Guillain-Barre syndrome peripheral neuropathy, and Bickerstaff brainstem encephalitis that occurred weeks after respiratory symptoms.

The clinical cases

A COVID-19 positive patient experienced seizures, although she had no history of alcohol/drug abuse or epilepsy. In another case, the patient had an altered mental condition, and the final diagnosis was acute necrotizing encephalopathy associated with SARS-CoV-2 infection.

Likewise, the reviewers have collated such cases that involve any of these manifestations: meningeal irritation, encephalitis with SARS-CoV-2 in the CSF, inflammation of the brain and spinal cord, ataxia (damage to the cerebellum), impaired consciousness and acute cerebrovascular diseases, encephalopathy or constant change in consciousness, etc. In the case of reduced taste and smell, the virus can disrupt the cranial nerves which may lead to chemosensory dysfunction affecting taste sensation.

Moreover, SARS-CoV-2 may be latent in the CNS. Therefore, the reviewers bring attention to the possibility of "cured" patients suffering from neurological diseases later in time; this warrants further investigations.

Invasion of SARS-CoV-2 into the brain

The ACE2 (angiotensin-converting enzyme II) receptor - essential for the SARS-CoV-2 entry into the host cell - is also found in the brain.

Among possible routes of entry into the CNS, the virus may enter the olfactory nerves via the ACE2 and migrate along the neuroepithelial route to reach the brain (as evident by the loss of smell in COVID-19 patients) or via the blood-brain barrier by binding to the ACE2 on the endothelial cells and traversing the highly selective barrier, the reviewers write.

The Cytokine storms associated with severe SARS-CoV-2 infection, high fever and inflammation may increase the blood-brain barrier's permeability. The general blood circulation and ACE2 expressed in capillary endothelium is one possible route to enter the brain.

The virus might also reside inside the "Trojan horse of the microbial world," such as the resilient Acanthamoeba castellanii and other cells such as the bloodstream leukocytes, dendritic cells and myeloid cells. Through these carriers or reservoirs of the virus, it is suggested that the SARS-CoV-2 may gain entry into the CNS.

ACE2 in the brain

The host tropism of coronaviruses is determined by the Spike (S) protein of the virus. And also the presence of the ACE2. The expression of ACE2 is high in the substantia nigra and brain ventricles, as well as both excitatory and inhibitory neurons in the middle temporal gyrus and posterior cingulate cortex. It is also present in the brain nuclei of essential cells and hypothalamic areas, Piriform cortex (associated with the sense of smell), hippocampal regions and excitatory neurons.

Significance and impact

Though the brain is immune privileged, it is now established that SARS-CoV-2 enters brain cells. The role of vaccines in preventing and protecting the brain cells from infection is unclear. Under this purview, further studies of clinical trials along the vaccine rollout are required.

The reviewers also recommend that because the virus can transverse into the CNS, the drugs currently used for COVID-19 treatment need to be reviewed.

"The survivability of SARS-CoV-2 in free-living amoebae warrants further studies since studies will reveal if the amoebae have a role as facilitators for the transmission of the virus or protection of the virus during treatment which might be responsible for relapses."

Given the heterogeneous complications within the nervous system, it is important to confirm whether patients are suffering from SARS-CoV-2 infection with neurological involvement.

Conclusion

Mounting evidence suggests that it invades the CNS; patients show symptoms related to brain infection. It is also found in the cerebrospinal fluid (CSF). The parietal lobe and the cerebellum appear to be the likely targets of SARS-CoV-2. Further studies related to this are warranted to arrive at conclusions.

These findings need to be considered when treating COVID-19 patients, the reviewers inform.

Journal reference:
Dr. Ramya Dwivedi

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.

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