Severe Acute Respiratory Syndrome Coronavirus 2, Olfactory Mucosa, and the Entrance in the Central Nervous System: Expanding the Evidence?

Abstract

Meinhardt, J, Radke, J, Dittmayer, C, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 2021; 24( 2): 168– 175. https://doi.org/10.1038/s41593-020-00758-5. The world faces a unique and historic challenge as a result of the pandemic associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Beyond the respiratory compromise, SARS-CoV-2 infection produces a myriad of neurological manifestations that have been progressively characterized.1 These neurological manifestations can potentially be (1) a consequence of the pulmonary and systemic disease, (2) attributed to a postinfectious (immune-mediated) mechanism, or (3) related to the direct viral central nervous system (CNS) invasion (either via trans-synaptic spreading or through the disruption of the blood–brain barrier). The lack of detection of SARS-CoV-2 in the cerebrospinal fluid in most patients with coronavirus disease 2019 (COVID-19)–related encephalitis, despite evidence of brain inflammation, suggests an immune-mediated mechanism rather than a direct viral invasion.1, 2 The neurotropism of coronaviruses is known and the recent detection of viral RNA in the brains of a subset of patients with COVID-19 led to the hypothesis of SARS-CoV-2 to reach the CNS. Because of the high number of patients with COVID-19 experiencing hyposmia, the trans-synaptic olfactory pathway has been pointed to as the route for entry into the CNS.3 A ramification of this theory affecting us, movement disorders experts, is the hypothetical link between SARS-CoV-2 infection and Parkinson's disease development.4 The featured article by Meinhardt and colleagues5 represents the most extensive postmortem study published so far. The authors assessed the olfactory mucosa and several defined CNS regions to address the important question of whether the olfactory mucosa acts as an entrance for SARS-CoV-2 into the CNS.5 The rather comprehensive evaluation of the tissue samples from 33 patients who died in the context of severe COVID-19 infection included detailed histological and genetic assessments. As a first step, the authors mapped the regional presence of SARS-CoV-2 RNA by real-time quantitative polymerase chain reaction and subgenomic RNA. Interestingly, the olfactory mucosa revealed the highest viral load compared with other tissue samples such as the oral mucosa or trigeminal ganglion. Only active viral replication was identified in the olfactory and oral mucosa. In additional analyses, the SARS-CoV-2 RNA in situ hybridization technique showed intense signaling in the mucous layer and cells of the olfactory epithelium, whereas it was absent in the olfactory sensory neurons. In line with this result, the ultrastructural imaging using electron microscopy showed both extracellular and intracellular viral particles within different cellular compartments of the olfactory epithelium. To further characterize which cells within the olfactory mucosa were invaded by the virus, they performed immunofluorescence colocalization studies. Remarkably, in 3 of 33 patients, the authors found colocalization of the SARS-CoV-2 spike protein with Olig2, an oligodendrocyte marker. This finding provided evidence of the presence of the viral protein in the olfactory sensory neurons. Finally, SARS-CoV-2 was not found in the neuronal or glial cells of the CNS parenchyma of the studied patients. Overall, these data suggested that in the absence of angiotensin-converting enzyme 2 receptors, such as in the olfactory neuronal cells, SARS-CoV-2 infection could be mediated through a transcytosis mechanism: from the olfactory mucosa cells to the olfactory neuronal cells. However, it cannot be discarded that other receptors may facilitate cell entry and infectivity.6 Furthermore, the virus could have been transported through the blood vessels into the brain, as the virus was also found in blood vessel endothelium. The extent to which the virus might have spread into the CNS in those 3 cases remains speculative, as neither viral RNA within the brain parenchyma or neuron-to-neuron propagation were shown. In summary, these results provide evidence that SARS-CoV-2 neuroinvasion can occur at the olfactory neural–mucosal interface. This critical aspect may help to characterize further the extension and mechanisms underlying the entry and action of SARS-CoV-2 in the brain. Broader CNS sampling studies also elucidating the molecular details of SARS-CoV-2 infection and its repercussions in the human brain are needed. Ethical Compliance Statement: Informed patient consent was not necessary for this work. The approval of an institutional review board was not required. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. There are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: M.H.G.M. is an employee of the Department of Neurology, Northwestern University Feinberg School of Medicine and has received honoraria from the Autonomous University of Madrid and HM-Puerta del Sur University Hospital and speaker honoraria from Novartis Pharmaceutical.