Smeet Solanki1*, Hani Choksi2*
1Honours Psychology, Neuroscience & Behaviour, Class of 2022, McMaster University firstname.lastname@example.org
2Chemical Biology Co-op, Class of 2022, McMaster University
*authors contributed equally to this work
COVID-19 is the current global pandemic that has affected millions around the world. While it appears that respiratory distress such as fever, dry cough, lung inflammation, and pneumonia are common symptoms among COVID-19 patients, neurological symptoms such as anosmia and ageusia are also becoming more common. The COVID-19 virus targets the hACE2 for initial recognition and host entry, while also showing an enhanced binding affinity for hACE2 in humans compared to its predecessors. Since the brain possesses this hACE2 receptor, it is also susceptible to infection from the COVID-19 virus. The novel virus can travel to the brain by penetrating the blood-brain barrier through the lungs (using the vagal nerve), and the GI tract (using the enteric nervous system) causing severe neural degeneration, resulting in neurodegenerative diseases like Parkinson’s disease, schizophrenia, and multiple sclerosis. A firm understanding of the underlying mechanisms and pathways behind the COVID-19 virus is crucial in order to identify individuals at-risk for these neurological complications and explore target interventions.
COVID-19 (coronavirus disease 2019) is the current global pandemic that has brought havoc around the world. After the first reported case in Wuhan, China, it has been spreading rapidly since December 2019 and has affected 212 countries as of May 2020.1 Infected individuals are asymptomatic or display symptoms such as fever, dry cough, difficulty in breathing, chronic inflammation of the lungs, and pneumonia. In more vulnerable patients, this may escalate to a complete lung failure. While it appears that respiratory distress is a symptom prevalent among COVID-19 patients, recent studies report that neurological symptoms such as anosmia (partial or complete loss of sense of smell) and ageusia (complete loss of taste function of the tongue) are also becoming more common.1,3,4 A study involving 214 COVID-19 patients reports neurological manifestations in 36.4% of the patients, further hinting that in addition to the respiratory system, the nervous system may also be a potential target of the virus.5,6
The virus strain of COVID-19 is known as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Previously occurring strains include SARS-CoV, which was responsible for the Middle East respiratory syndrome (MERS) and the SARS outbreak. Like SARS-CoV, the COVID-19 virus exploits the human angiotensin-converting enzyme-2 receptor (hACE2) for initial recognition and host entry.7 Unlike the previous SARS-CoV, the novel virus has a selective advantage over its predecessor in causing inflection and virulence due to an enhanced binding affinity for hACE2 in humans.2 The hACE2 entry point is present ubiquitously throughout the body. Major bodily tracts and organs are reported as being “hot spots” for the virus due to their higher expression of hACE2. This includes the lungs parenchyma, nasal mucosa, gastrointestinal tract (GI tract), and the brain.
Like most organs in the body, the brain expresses the hACE2 protein, and thus is also susceptible to infection from the COVID-19 virus. There are several mechanisms through which this infection can occur. It has been noted that patients infected with SARS-CoV-2 suffer from severe acute respiratory syndrome. As the respiratory tract is connected to the Central Nervous System (CNS) through the vagal nerve, it is possible for the virus to travel in a retrograde manner from the lungs to the CNS.8,9 Reports indicate that patients prone to infection of the GI tract by SARS-CoV-2 are also at risk for the spread of the virus to the CNS. This occurs due to the possibility of the virus traveling from the GI tract to the CNS through the enteric nervous system and its afferent neurons.10 Further research needs to be conducted on the mechanisms and long-term implications of SARS-CoV-2 induced CNS infections, however, some trends can be elucidated from studies on the closely related SARS-CoV virus.
If SARS-CoV-2 follows the same trends as its predecessors, it will first affect the peripheral nervous system (PNS) and then enter the CNS. The blood-brain barrier is a filtering mechanism composed of capillaries which carry blood to the CNS and block the passage for pathogenic substances.3,4 Previous studies show that the SARS-CoV virus was detected in the cerebrospinal fluid (CSF) of infected patients. Therefore, it is likely that other viruses from the CoV family, such as SARS-CoV-2, may also have the ability to break the rigid blood-brain barrier and infect the brain. CT and MRI scans of the brains of COVID-19 patients display the underlying neurological effects that the virus may cause in the CNS. Acute necrotizing encephalopathy (ANE) is a rare brain disorder which causes excess secretion of cytokine and results in hyperinflammation.4,9,10 It has been associated with other viral infections but has recently been reported in association with COVID-19. Structures of the brain typically affected by ANE include; brain stem, thalamus, cerebellum, medulla oblongata, and cerebral white matter. Scientists also speculate that patient complaints regarding breathing problems may be from chronic damage to the neurons of the medulla oblongata, which regulate involuntary functions, such as breathing, lung and heart functions. The latency period of the virus is deemed enough to destroy neurons of the medulla oblongata, resulting in a coma or death.
It is difficult to predict the long-term effects of the neuroinvasive nature of SARS-CoV-2, however based on the trends of SARS-CoV and influenza outbreaks, scientists suspect that due to the latency period of SARS-CoV-2, prolonged exposure causes neuronal damage in many parts of the nervous system and results in neurodegenerative diseases like Parkinson’s disease, schizophrenia, and multiple sclerosis. COVID-19 has infected 3.71 million individuals of the world’s population and hence controlling this outbreak will require a global effort.1 According to the 2020 study by Das et al., even if delayed neurodegenerative sequelae affect a fraction of cases, public health impacts of these complications will be severe.2 For this reason, it is critical to direct research initiatives to further understand the neuropsychiatric outcomes that may stem from the infection of SARS-CoV-2. It is also equally important to understand the underlying mechanisms and pathways behind these infections for target interventions.
1. Blyuss, K. B., & Kyrychko, Y. N. (2020). Effects of latency and age structure on the dynamics and containment of COVID-19. medRxiv.
2. Das, G., Mukherjee, N., & Ghosh, S. (2020). Neurological Insights of COVID-19 Pandemic. ACS Chemical Neuroscience.
3. Baig, A. M., Khaleeq, A., Ali, U., & Syeda, H. (2020). Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS chemical neuroscience, 11(7), 995-998.
4. Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., & Perlman, S. (2008). Severe acute respiratory syndrome virus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. Journal of virology, 82(15), 7264-7275.
5. Troyer, E. A., Kohn, J. N., & Hong, S. (2020). Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain, behavior, and immunity.
6. Surveillances, V. (2020). The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)—China, 2020. China CDC Weekly, 2(8), 113-122.
7. Peeri, N. C., Shrestha, N., Rahman, M. S., Zaki, R., Tan, Z., Bibi, S., … & Haque, U. (2020). The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned?. International journal of epidemiology.
8. McCullough, P. A., Eidt, J., Rangaswami, J., Lerma, E., Tumlin, J., Wheelan, K., … & Singh, B. (2020). Urgent need for individual mobile phone and institutional reporting of at home, hospitalized, and intensive care unit cases of SARS-CoV-2 (COVID-19) infection. Reviews in cardiovascular medicine, 21(1), 1-7.
9. Li, Y. C., Bai, W. Z., & Hashikawa, T. (2020). The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients. Journal of medical virology.
10. Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R., & Begley, D. J. (2010). Structure and function of the blood–brain barrier. Neurobiology of disease, 37(1), 13-25.