Mechanisms of coronavirus infectious disease 2019-related neurologic diseases

Abstract

Purpose of reviewAs of January 8, 2022, a global pandemic caused by infection with severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a new RNA virus, has resulted in 304,896,785 cases in over 222 countries and regions, with over 5,500,683 deaths (www.worldometers.info/coronavirus/). Reports of neurological and psychiatric symptoms in the context of coronavirus infectious disease 2019 (COVID-19) range from headache, anosmia, and dysgeusia, to depression, fatigue, psychosis, seizures, delirium, suicide, meningitis, encephalitis, inflammatory demyelination, infarction, and acute hemorrhagic necrotizing encephalopathy. Moreover, 30--50% of COVID-19 survivors develop long-lasting neurologic symptoms, including a dysexecutive syndrome, with inattention and disorientation, and/or poor movement coordination. Detection of SARS-CoV-2 RNA within the central nervous system (CNS) of patients is rare, and mechanisms of neurological damage and ongoing neurologic diseases in COVID-19 patients are unknown. However, studies demonstrating viral glycoprotein effects on coagulation and cerebral vasculature, and hypoxia-and cytokine-mediated coagulopathy and CNS immunopathology suggest both virus-specific and neuroimmune responses may be involved. This review explores potential mechanistic insights that could contribute to COVID-19-related neurologic disease. Recent findingsWhile the development of neurologic diseases during acute COVID-19 is rarely associated with evidence of viral neuroinvasion, new evidence suggests SARS-CoV-2 Spike (S) protein exhibits direct inflammatory and pro-coagulation effects. This, in conjunction with immune dysregulation resulting in cytokine release syndrome (CRS) may result in acute cerebrovascular or neuroinflammatory diseases. Additionally, CRSmediated loss of blood-brain barrier integrity in specific brain regions may contribute to the expression of proinflammatory mediators by neural cells that may impact brain function long after resolution of acute infection. Importantly, host co-morbid diseases that affect vascular, pulmonary, or CNS function may contribute to the type of neurologic disease triggered by SARS-COV-2 infection. SummaryDistinct effects of SARS-CoV-2 S protein and CNS compartment-and region-specific responses to CRS may underlie acute and chronic neuroinflammatory diseases associated with COVID-19.

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“…Several studies investigated the capability of SARS-CoV-2 to directly invade and damage neurons and to reappear later with neurological diseases, like herpes simplex virus, but with a lack of evidence for productive infection of the CNS parenchyma [ 2 ]. Accordingly, anatomopathological findings suggest that the neuronal damage and loss are unlikely to be caused by a viral infection of brain tissue [ 2 ]. Furthermore, a direct viral neuroinvasion in the brain is not supported by CSF findings in the literature and in patient 1 of our study, who tested negative for CSF Sars-COV-2 mRNA detection.…”

“…Furthermore, a direct viral neuroinvasion in the brain is not supported by CSF findings in the literature and in patient 1 of our study, who tested negative for CSF Sars-COV-2 mRNA detection. Differently, para-infectious/post-infectious immune-mediated mechanisms induced by systemic SARS-CoV-2 infection appear to be a predominant pathogenic mechanism of neurological involvement [ 2 ].…”

“…It is plausible that systemic inflammatory effects and altered immune responses induced by SARS-CoV-2 disrupt the blood–brain barrier integrity and exert a negative impact on cerebral homeostasis and function, favoring neuronal degeneration in susceptible patients [ 2 ]. Notably, long-lasting inflammatory processes have been shown to develop within the CNS after several viral infections and might trigger or accelerate subclinical mechanisms that underlie an earlier onset of neurodegenerative disorders in individuals already at risk [ 2 ].…”

“…It is plausible that systemic inflammatory effects and altered immune responses induced by SARS-CoV-2 disrupt the blood–brain barrier integrity and exert a negative impact on cerebral homeostasis and function, favoring neuronal degeneration in susceptible patients [ 2 ]. Notably, long-lasting inflammatory processes have been shown to develop within the CNS after several viral infections and might trigger or accelerate subclinical mechanisms that underlie an earlier onset of neurodegenerative disorders in individuals already at risk [ 2 ]. Nonetheless, neuroinflammation is one hallmark of HD [ 6 ], mediated through the cytokine expression and the activation of microglia and astrocytes in the striatum and cortex which have been correlated both with the pathology and severity of HD and are already evident in presymptomatic HD mutation carriers [ 7 ].…”

“…Imaging and cerebrospinal fluid (CSF) studies in such patients suggest a possible underlying post-viral immune mechanism, ruling out structural brain lesions and encephalitic processes [ 1 ]. Interestingly, SARS-CoV-2 infection appears to be able to affect several crucial cellular pathways, which are also relevant in cellular aging and in neurodegenerative diseases [ 2 ]. These include immune activation and inflammation.…”