Neurotropism of SARS-CoV-2 and neurological diseases of the central nervous system in COVID-19 patients

Abstract

The devastating COVID-19 pandemic is caused by the SARS-CoV-2 virus. It primarily affects the lung and induces acute respiratory distress leading to a decrease in oxygen supply to the cells. This lung insufficiency caused by SARS-CoV-2 virus contributes to hypoxia which can affect the brain and other organ systems. The heightened cytokine storm in COVID-19 patients leads to an immune reaction in the vascular endothelial cells that compromise the host defenses against the SARS-CoV-2 virus in various organs. The vascular endothelial cell membrane breach allows access for SARS-CoV-2 to infect multiple tissues and organs. The neurotropism of spike protein in SARS-CoV-2 rendered by furin site insertion may increase neuronal infections. These could result in encephalitis and encephalopathy. The COVID-19 patients suffered severe lung deficiency often showed effects in the brain and neural system. The early symptoms include headache, loss of smell, mental confusion, psychiatric disorders and strokes, and rarely encephalitis, which indicated the vulnerability of the nervous system to SARS-CoV-2. Infection of the brain and peripheral nervous system can lead to the dysfunction of other organs and result in multi-organ failure. This review focuses on discussing the vulnerability of the nervous system based on the pattern of expression of the receptors for the SARS-CoV-2 and the mechanisms of its cell invasion. The SARS-CoV-2 elicited immune response and host immune response evasion are further discussed. Then the effects on the nervous system and its consequences on neuro-sensory functions are discussed. Finally, the emerging information on the overall genetic susceptibility seen in COVID-19 patients and its implications for therapy outlook is discussed.

Keywords: Encephalopathy; Furin; Neural diseases; Neurotropism; SARS-CoV-2.

Fig. 1

Schematic of the SARS-CoV-2 virus, Spike protein and ACE2 receptor with furin site. a The SARS-CoV-2 structure of the virus showing single (plus) strand RNA with its envelope (E), membrane (M) protein, nucleocapsid (N), and spike (S) protein. The S bound with Angiotensin-Converting Enzyme -2 (ACE2) is depicted. RBD is the receptor-binding domain, S1-CTD and S1-NTD are C-terminal and N-terminal domains of S1. S2 is the C-terminal part of the spike. b The spike protein structure with furin cleave site and other components. RBD is as above. S1/S2 is the junction of the S1 and S2 domains. S2’ contains a furin cleavage site with the unique amino acid sequence PRRA present in SARS-CoV-2. FP is the fusion peptide, HR1 and HR2 are heptad repeats, TM is a transmembrane domain. (a is created with BioRender.com)

Fig. 2

The ACE2 receptor-expressing tissues and organs and effect of SARS-CoV-2 infection in these targets. The SARS-CoV-2 infection affects mainly the lung with ARDS and respiratory failure. The brain is also affected by stroke and encephalopathy. The encephalopathy may be due to encephalitis, which is not completely established. The vascular endothelial cells are damaged in COVID-19 patients and it could affect many tissues and organs. The detailed effects are listed in the figure. (The image is created with BioRender.com)