Effects of COVID-19 on the Nervous System

Costantino Iadecola, Josef Anrather, Hooman Kamel, Costantino Iadecola, Josef Anrather, Hooman Kamel

Abstract

Neurological complications have emerged as a significant cause of morbidity and mortality in the ongoing COVID-19 pandemic. Beside respiratory insufficiency, many hospitalized patients exhibit neurological manifestations ranging from headache and loss of smell, to confusion and disabling strokes. COVID-19 is also anticipated to take a toll on the nervous system in the long term. Here, we will provide a critical appraisal of the potential for neurotropism and mechanisms of neuropathogenesis of SARS-CoV-2 as they relate to the acute and chronic neurological consequences of the infection. Finally, we will examine potential avenues for future research and therapeutic development.

Conflict of interest statement

Declaration of Interests C.I. serves on the Scientific Advisory Board of Broadview Ventures. H.K. serves as co-PI for the NIH-funded ARCADIA trial (NINDS U01NS095869) that receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics, serves as Deputy Editor for JAMA Neurology, serves as a steering committee member of Medtronic’s Stroke AF trial (uncompensated), serves on an endpoint adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim, and has served on an advisory board for Roivant Sciences related to Factor XI inhibition. J.A. has no conflict of interests to declare.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Expression Profiles of Selected Genes Relevant to SARS-CoV-2 Brain Entry In a single nuclear RNA-seq profile of human cortical brain tissue (https://celltypes.brain-map.org) (Hodge et al., 2019), there was no evidence of ACE2 expression in any brain cell type. Basigin (BSG) was prominently expressed in pericytes and endothelial cells, whereas neuropilin-1 (NRP1) was detected in endothelial cells and in several classes of excitatory neurons. Low expression of TMPRSS11A and FURIN was found in neurons, whereas CSTB was moderately expressed in most cell types with the exception of astrocytes and oligodendrocytes and their precursors. Endothelial cells and pericytes also express lymphocyte antigen 6 family member E (LY6E) and the interferon (IFN)-induced transmembrane proteins-1 and 3 (IFITM1, IFITM3), which have been shown to restrict SARS-CoV-2 cell entry (Hachim et al., 2020; Pfaender et al., 2020; Zhao et al., 2020). IFN type I receptors (IFNRA1 and IFNRA2) showed higher expression in endothelial cells than in other cell types. Cell cluster annotations are from (Hodge et al., 2019). CPM, transcript counts per million within the cell cluster; FracCellExpr, fraction of cells in which the transcript is detected.
Figure S1
Figure S1
Expression Profiles of Selected Genes Relevant to SARS-CoV-2 Brain Entry in Single Nuclear RNA-Seq Profiles of Human Brain Tissue, Related to “Brain Expression of SARS-CoV-2 Receptors and Related Proteins” A, count matrix and cluster annotations are from https://portal.brain-map.org/atlases-and-data/rnaseq/human-m1-10x. The data set is composed of 76,533 total nuclei of the primary motor cortex derived from 2 post-mortem human brain specimens. B, count matrix and cluster annotations are from the Gene Expression Omnibus submission GSE97942 (Lake et al., 2018). The data set is composed of 35,289 nuclei collected from frontal cortex, visual cortex, and cerebellum from 6 post-mortem human brain samples. CPM, transcript counts per million transcripts within the cell cluster; FracCellExpr, fraction of cells in which the transcript is detected. Data analysis was performed in the R (Vers. 4.02) statistical environment using tidyverse (Vers. 1.3.0) and Seurat (Vers. 3.2.0) packages.
Figure 2
Figure 2
Potential Mechanisms of Vascular Damage and Brain Entry of SARS-CoV-2 Circulating virus, cytokines, DAMPs, and PAMPs could act on endothelial cells, leading to inflammation and opening of the BBB. Once in the perivascular space and these factors could induce inflammation in vascular mural cells and brain resident myeloid cells (microglia and macrophages). The resulting cytokine production could affect neuron neuronal function leading to the cytokine sickness, a potential cause of encephalopathy in COVID-19.
Figure 3
Figure 3
Potential Role of the HPA Axis in the Immune Dysregulation of COVID-19 Cytokine and SARS-CoV-2 entry into the median eminence of the hypothalamus could lead to activation of the autonomic nervous system and release of adrenal catecholamines and steroids. In analogy with stroke, brain trauma, and myocardial infarction (Iadecola et al., 2020), these neurohumoral effectors could act on the bone marrow to release immunosuppressor neutrophils and myeloid cells (emergency myelopoiesis), as described in COVID-19 (Schulte-Schrepping et al., 2020), leading to immunosuppression and lymphopenia. In addition, release of calprotectin and cytokines from damaged lungs could also contribute to emergency myelopoiesis (Silvin et al., 2020).

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Source: PubMed

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