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Review
. 2021 Aug;29(4):939-963.
doi: 10.1007/s10787-021-00806-x. Epub 2021 Apr 6.

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

Menizibeya O Welcome  1 , Nikos E Mastorakis  2
Affiliations
Review

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

Menizibeya O Welcome et al. Inflammopharmacology. 2021 Aug.

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.

Keywords: Blood brain barrier disruption; COVID-19; Neuroinfection; Neuroinflammation; Neuropathogenesis; SARS-CoV-2.

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Conflict of interest statement

None declared.

Figures

Fig. 1
Fig. 1
Schematic representation of SARS-CoV-2 invasion of olfactory/nasopharyngeal, pulmonary, intestinal and tongue or oropharyngeal epithelial cells. ACE2 angiotensin converting enzyme 2, ER endoplasmic reticulum, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, TMPRSS2 transmembrane protease, serine 2 (see explanation in text)
Fig. 2
Fig. 2
Mechanisms involved in SARS-CoV-2 induced neuroinfection, neuroinflammation and neurodegeneration. ACE2 angiotensin converting enzyme 2, AJ adherens junction, BBB blood brain barrier, CCL-2 C–C motif chemokine ligand, cJNK c-Jun N-terminal kinase, CXCL-8 C-X-C motif chemokine ligand, Fas FS-7-associated surface antigen, IFN-γ interferon gamma, IL interleukin, iNOS inducible nitric oxide synthase, IP-10 IFNγ-induced protein 10, MAPK mitogen-activated protein kinase, MCP-1 monocyte chemoattractant protein-1, MIP-1A macrophage inflammatory protein-1A, NADPH nicotinamide adenine dinucleotide phosphate, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NLRP3 nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, NO nitric oxide, P2X7R P2X purinergic receptor 7, PRR pattern recognition receptor, ROS reactive oxygen species, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, TGF-β transforming growth factor, TJ tight junction, TLR toll-like receptor, TMPRSS2 transmembrane protease, serine 2, TNF-α tumor necrosis factor alpha (see explanation in text)
Fig. 3
Fig. 3
Simplified schematic representation of SARS-CoV-2 infection of blood. MHC major histocompatibility complex, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, Th T helper, Treg T regulatory (see explanation in text)
Fig. 4
Fig. 4
JAK-STAT signalling in SARS-CoV-2 infection. IFN interferon, IL interleukin, JAK Janus kinase, MAP kinase mitogen activated protein kinase, PI-3-kinase phosphoinositide 3-kinase, Raf Rapidly Accelerated Fibrosarcoma (protein that interacts with small GTPases), STAT signal transducers and activators of transcription (see explanation in text)
Fig. 5
Fig. 5
TLR signalling in SARS-CoV-2 infection. ACE2 angiotensin converting enzyme 2, IFN interferon gamma, IPS-1 interferon-β promotor stimulator-1, IRE interferon regulatory element, IRF interferon regulatory factor, ISRE Interferon-sensitive response element, MAVS mitochondrial antiviral signalling protein, MDA5 melanoma differentiation-association gene 5, MyD88 myeloid differentiation primary response 88, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NLRP3 nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, ORF open reading frame, P2X7R P2X purinergic receptor 7, PPRγ peroxisome proliferator-activated receptor gamma, PRR pattern recognition receptor, RIG-1 retinoic acid inducible gene-I, ROS reactive oxygen species, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, TLR toll-like receptor, TMPRSS2 transmembrane protease, serine 2 (see explanation in text)
Fig. 6
Fig. 6
Fas signalling in SARS-CoV-2 infection. Atg5 autophagy 5 protein, bax Bcl-2-associated X protein, bcl-2 B-cell lymphoma 2-encoded protein, CD cluster of differentiation, FADD Fas-associated death domain, Fas FS-7-associated surface antigen, FasL Fas ligand, FasR Fas receptor, NK natural killer, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, TNFR tumor necrosis factor receptor, TRAIL TNF(tumor necrosis factor)-related apoptosis-inducing ligand (see explanation in text)
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