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Review
. 2020 Oct;26(5):619-630.
doi: 10.1007/s13365-020-00895-4. Epub 2020 Aug 24.

Neurological manifestations of COVID-19: available evidences and a new paradigm

Fatima Khatoon  1 , Kartikay Prasad  1 , Vijay Kumar  2
Affiliations
Review

Neurological manifestations of COVID-19: available evidences and a new paradigm

Fatima Khatoon et al. J Neurovirol. 2020 Oct.

Abstract

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

Keywords: COVID-19; Gene enrichment; Gene prioritization; Neurological damage; SARS-CoV-2.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
The mechanism of coronavirus infections and neurological damage caused by SARS-CoV-2. The coronavirus can enter the nervous system directly through the olfactory nerve, blood circulation, ACE2 in brainstem, immune injury, and neuronal pathways, resulting in neurological disorders. The COVID-19 infection in the gastrointestinal tract could use the enteric nervous system (ENS) and its sympathetic afferent neurons to reach the CNS
Fig. 2
Fig. 2
(a) Protein-protein interaction (PPI) network of 73 genes from 331 human SARS-CoV-2 interacting genes showing relation to brain-related diseases using the gene-organizer database. Red color nodes represent the hub proteins in the network. (b) Functional enrichment analysis of genes through GO and KEGG analysis
Fig. 3
Fig. 3
Disease-based enrichment analysis through the Enrichr web server. Gene set enrichment analysis of top genes obtained through (a) DisGNet, and (b) Jensen DISEASE
Fig. 4
Fig. 4
BEST results of the 73 genes. Spatio-temporal expression heatmap of genes (a) RNA-Seq BrainSpan dataset, and (b) RNA-Seq GTEx dataset; (c) cell-type enrichment heatmap according to RNA-Seq GTEx; (d) expression heatmap of enriched clusters; and (e) core co-expression network of enriched genes
Fig. 5
Fig. 5
Gene prioritization analysis through EvoTol. (a) The evolutionary intolerant gene expression in the nervous system and brain. (b) Enrichment of disease-causing genes in different human tissue-specific system. For each tissue-type, we identified robustly expressed genes as those whose average expression is > 100 TPM. (c) GeneMANIA network of the five putative pathogenic genes
Fig. 6
Fig. 6
(a) Interaction of 73 genes with COVID-19 receptors. ITGB1 gene showing interaction with ACE2 receptor (square shaped) along with 3 hubs genes of the network (hexagon-shaped). (b) ITGB1 expression levels across the six brain regions over the human life span are shown as obtained from HBT
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