Viral entry and potential neurological consequences
The viruses associated with both SARS and COVID-19 enter the brain via a process involving the angiotensin-converting enzyme (ACE)-2 receptors located in the CNS [17–19], unlike the MERS virus, which gains entry via the plasma membrane or in the endosomes [20]. ACE-2 receptors are expressed in many parts of the body and are particularly densely expressed in the nasal mucosa. Coronaviruses that enter the body via the nasal mucosa may disrupt the nasal endothelium, cross the epithelial barrier, and then directly enter the lymphatic or circulatory system, accessing the CNS [21]. The SARS-CoV has been detected in the brain, and it is thought entry occurred by way of the olfactory nerve. Since there have been studies that located the SARS-CoV virus in the CNS but not the lung, it suggests that there is a direct pathway from the olfactory point of entry into the CNS [22]. Alternatively, a high viral load in the brain following a pulmonary infection might mean the virus entered the brain from the respiratory system; e.g., the vagus nerve links the respiratory system to the nucleus ambiguous and solitary tract nuclei of the brainstem. It has been speculated that the cardiorespiratory center of the brain may be involved in the severe acute respiratory distress in some patients with COVID-19 [23]. The more common form of respiratory failure in COVID-19 patients is Type 1 (gas exchange dysfunction resulting in hypoxia and low levels of carbon dioxide), which is more likely to be associated with pneumonia than brain dysfunction [24]. Type 2 respiratory failure, which involves both hypoxia and high levels of carbon dioxide due to ventilatory failure would be more suggestive of neurological dysfunction, and this occurs less frequently in COVID-19 patients [25].
Any viral invader of the CNS creates stress within the body, because the host must balance its natural immune response to destroy the pathogen while, at the same time, minimizing damage to nearby nonrenewable cells [26]. Once in the CNS, viruses that affect neurons are far more dangerous than viruses that target the leptomeninges, which can restore themselves. The CNS has a highly nuanced system of responses to viruses, which can cause considerable harm to the body should it become uncontrolled.
Coronaviruses such as the SARS-CoV-2 can enter the body via the nasal mucosa and may disrupt the nasal endothelium, cross the epithelial barrier, and then enter the CNS via the lymphatic or circulatory system [21]. The blood-brain barrier has a pore size of about 1 nm and coronaviruses are substantially larger [9], and this likely protects the brain from coronavirus invasion in many individuals. However, neuroinvasive viruses can cross the blood-brain barrier by brain viremia, inflammatory processes (making microvascular endothelial cells vulnerable), or infecting leukocytes that then cross the blood-brain barrier in the manner of a Trojan horse [27]. The entry of the virus via the olfactory endothelium with transit of the virus across the cribriform plate would allow the virus to enter the brain by circumventing the blood-brain barrier entirely [27].
In theory at least, the coronavirus could invade the CNS using a passive mechanism such as hematogenous spread; in this case, the virus goes dormant and is carried toward the CNS, only to re-activate at some point to infect endothelial cells of the blood-brain barrier or infect leukocytes that then act as the reservoir for further viral dissemination [28]. The neurological symptoms associated with the H1N1 influenza virus had earlier been explained by an autoimmunity model [29]. The autoimmunity model of coronavirus infection of the CNS, likewise unproven, maintains that neural tissues and blood vessels perceive both viral and myelin antigens as the same because of autoreactive T-cells. Autoimmunity would be limited to patients who were genetically predisposed [29].
The SARS-CoV-2 associated with COVID-19 belongs to the same clade of beta-coronaviruses as the MERS-CoV and the SARS-CoV viruses, although its homological sequence more closely resembles SARS-CoV than MERS-CoV [2]. The respiratory symptoms that occur in genetically related beta-coronaviruses, such as MERS-CoV and SARS-CoV are similar, two infections with which the global healthcare community has had years of clinical experience [30]. While it cannot be stated unequivocally that the neurological symptoms of these viral infections will be the same, it forms a good starting point.