Neuropathophysiology of coronavirus disease 2019: neuroinflammation and blood brain barrier disruption are critical pathophysiological processes that contribute to the clinical symptoms of SARS-CoV-2 infection

Abstract

Coronavirus disease 2019 (COVID-19) is caused by the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) first discovered in Wuhan, Hubei province, China in December 2019. SARS-CoV-2 has infected several millions of people, resulting in a huge socioeconomic cost and over 2.5 million deaths worldwide. Though the pathogenesis of COVID-19 is not fully understood, data have consistently shown that SARS-CoV-2 mainly affects the respiratory and gastrointestinal tracts. Nevertheless, accumulating evidence has implicated the central nervous system in the pathogenesis of SARS-CoV-2 infection. Unfortunately, however, the mechanisms of SARS-CoV-2 induced impairment of the central nervous system are not completely known. Here, we review the literature on possible neuropathogenic mechanisms of SARS-CoV-2 induced cerebral damage. The results suggest that downregulation of angiotensin converting enzyme 2 (ACE2) with increased activity of the transmembrane protease serine 2 (TMPRSS2) and cathepsin L in SARS-CoV-2 neuroinvasion may result in upregulation of proinflammatory mediators and reactive species that trigger neuroinflammatory response and blood brain barrier disruption. Furthermore, dysregulation of hormone and neurotransmitter signalling may constitute a fundamental mechanism involved in the neuropathogenic sequelae of SARS-CoV-2 infection. The viral RNA or antigenic peptides also activate or interact with molecular signalling pathways mediated by pattern recognition receptors (e.g., toll-like receptors), nuclear factor kappa B, Janus kinase/signal transducer and activator of transcription, complement cascades, and cell suicide molecules. Potential molecular targets and therapeutics of SARS-CoV-2 induced neurologic damage are also discussed.

Post-acute sequelae of COVID-19: Evidence of mood & cognitive impairment

“…Some have postulated that neurological sequelae of COVID-19 could reflect direct actions of SARS-CoV-2 on the brain ( Boldrini et al, 2021 ; Saleki et al, 2020 ). Indeed, SARS-CoV-2 mRNA has been detected in cerebrospinal fluid (CSF; Moriguchi & Mastorakis, 2020 ), suggesting the virus could either damage ( Welcome et al, 2021 ) or permeate ( Rhea et al, 2021 ) the blood-brain barrier (BBB). To this extent, some have attributed neuropsychiatric manifestations of COVID-19 to disruptions in the BBB that result in atrophy to neural and glial cells ( Alonso-Lana et al, 2020 ).…”

Molecular Mechanisms of Palmitic Acid Augmentation in COVID-19 Pathologies

“…SARS-CoV-2 infection of the brainstem may also cause respiratory center dysfunctions [59]. Dysregulation of hormone and neurotransmitter signaling have also been suggested to contribute to the neuropathogenic sequelae of SARS-CoV-2 infection [60]. While the mechanisms by which SARS-CoV-2 impairs the CNS are not completely known, neuroinflammation and blood-brain barrier (BBB) disruption have been suggested to contribute to neurological symptoms and poor prognosis [60][61][62].…”

“…Dysregulation of hormone and neurotransmitter signaling have also been suggested to contribute to the neuropathogenic sequelae of SARS-CoV-2 infection [60]. While the mechanisms by which SARS-CoV-2 impairs the CNS are not completely known, neuroinflammation and blood-brain barrier (BBB) disruption have been suggested to contribute to neurological symptoms and poor prognosis [60][61][62]. Indeed, profound neuroinflammatory changes have been reported in COVID-19 patients [63], which could be due to direct infection of the CNS, microglia activation, and activated peripheral immune response to SARS-CoV-2 infection [56,64], all of which could be worsened by obesity [65,66].…”

The Immunopathogenesis of Neuroinvasive Lesions of SARS-CoV-2 Infection in COVID-19 Patients

“…This mechanism is observed with viruses such as hepatitis E virus (28) and encephalitic alpha viruses (29). Because of the high expression of ACE2 in cellular components of the BBB, it is suggested that the disruption of BBB by SARS-CoV-2 may play the main role in the central and peripheral nervous system damage seen in severe COVID-19 (30).…”