Elucidating the Neuropathologic Mechanisms of SARS-CoV-2 Infection

Abstract

The current pandemic caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a public health emergency. To date, March 1, 2021, coronavirus disease 2019 (COVID-19) has caused about 114 million accumulated cases and 2.53 million deaths worldwide. Previous pieces of evidence suggest that SARS-CoV-2 may affect the central nervous system (CNS) and cause neurological symptoms in COVID-19 patients. It is also known that angiotensin-converting enzyme-2 (ACE2), the primary receptor for SARS-CoV-2 infection, is expressed in different brain areas and cell types. Thus, it is hypothesized that infection by this virus could generate or exacerbate neuropathological alterations. However, the molecular mechanisms that link COVID-19 disease and nerve damage are unclear. In this review, we describe the routes of SARS-CoV-2 invasion into the central nervous system. We also analyze the neuropathologic mechanisms underlying this viral infection, and their potential relationship with the neurological manifestations described in patients with COVID-19, and the appearance or exacerbation of some neurodegenerative diseases.

COVID-19 as a Trigger of Brain Autoimmunity

“…The clinical manifestations of autoimmune neurological disorders such as multiple sclerosis (MS) or Guillain–Barré syndrome (GBS) have been reported in COVID-19 case studies. 3 For example, following 2–3 weeks of SARS-CoV-2 infection a 29-year-old female developed multiple sclerosis with right optic neuritis; 4 MS-like demyelination may occur in COVID-19 patients due to autoimmune mechanisms resulting from T-lymphocyte activation secondary to M1 microglia phenotype activation with associated inflammatory mediator release. As presented in another case report, myelin oligodendrocyte glycoprotein antibody-positive neuromyelitis optica was observed in a 26-year-old male who presented with bilateral optic neuritis and extensive longitudinal transverse myelitis, occurring several days after COVID-19 symptom onset.…”

Potential Cross-Links of Inflammation With Schizophreniform and Affective Symptoms: A Review and Outlook on Autoimmune Encephalitis and COVID-19

“…IL-6-dependent Th17 activation and differentiation is essential for neutrophil granulocyte migration ( 42 ). Experimental work showed that SARS-CoV-2-infected glial cells secrete increased levels of IL-6 and TNFα ( 5 , 43 ). IL-6 can alter neuronal and glial activity and induce cell death, olfactory loss or induction of hyperphosphorylation of the tau protein in axons, triggering their degeneration.…”

“…Microvascular damage in the systemic inflammatory response to SARS-CoV-2 is thought to promote the occurrence of encephalopathy in severe COVID-19 disease ( 5 ). Inflammatory mediators produced by the alveolar epithelium, macrophages and leukocytes may contribute to endothelial inflammation, increased vascular permeability, edema, and increased synthesis and consumption of coagulation factors.…”

“…Clots can trigger thromboembolic events of the cerebral arteries or sinus vein thrombosis. However, the increased vascular permeability also leads to disturbances of the microcirculation including BBB impairment ( 5 ). As mentioned above, BBB dysfunction may facilitate the entry of preformed or SARS-CoV-2-associated antineuronal autoantibodies from the periphery to the brain ( 28 , 29 ).…”

SARS-CoV-2 Infection and Guillain-Barré Syndrome

“…It could also be due to direct viral invasion of the nervous system. There are reports of SARS-CoV-2 detection in the CSF and in postmortem brain tissue, the latter even in the absence of respiratory illness [ 10 ]. Evidence of direct and widespread neural infection is still being investigated intensely.…”