Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System

Abstract

In late December 2019, multiple atypical pneumonia cases resulted in severe acute respiratory syndrome caused by a pathogen identified as a novel coronavirus SARS-CoV-2. The most common coronavirus disease 2019 (COVID-19) symptoms are pneumonia, fever, dry cough, and fatigue. However, some neurological complications following SARS-CoV-2 infection include confusion, cerebrovascular diseases, ataxia, hypogeusia, hyposmia, neuralgia, and seizures. Indeed, a growing literature demonstrates that neurotropism is a common feature of coronaviruses; therefore, the infection mechanisms already described in other coronaviruses may also be applicable for SARS-CoV-2. Understanding the underlying pathogenetic mechanisms in the nervous system infection and the neurological involvement is essential to assess possible long-term neurological alteration of COVID-19. Here, we provide an overview of associated literature regarding possible routes of COVID-19 neuroinvasion, such as the trans-synapse-connected route in the olfactory pathway and peripheral nerve terminals and its neurological implications in the central nervous system.

The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models

“…These findings do not support the hypothesis that SARS-CoV-2 invades the brain by multiple transfers from neuron to neuron, with the first transfer from olfactory receptor neurons to mitral cells in the olfactory bulb. The observed time course is more consistent with alternative routes of neuro-invasion [5,39,81]. Such alternative routes include a pathway that reaches cerebrospinal fluid (CSF)-containing spaces, uses the vasculature, or the virus may travel along a When in the same image the sustentacular cell body is invisible (black ellipsoid shadow with white arrows), as it would be when the plane of section is not entirely perpendicular to the epithelium, then the SARS-CoV-2 protein would be erroneously interpreted to be colocalized within the OMP-expressing olfactory receptor neuron.…”

The Role of the Gastrointestinal System in Neuroinvasion by SARS-CoV-2

“…The significantly high homology between SARS-CoV and SARS-CoV-2 also supports the potential of neural invasion by SARS-CoV-2 (Reza-Zaldivar et al, 2020;Meinhardt et al, 2021). Neuroinvasion may occur through the retrograde synaptic transmission of SARS-CoV-2 from the mechanical and chemical receptors of the lung to the medullary cardiopulmonary respiratory center (Li Y. C. et al, 2020).…”

“…Although the nervous system is compromised by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the underlying mechanism has not been elucidated. Based on the current literature and available case reports, there may be several routes for SARS-CoV-2 neuroinvasion: ( 1) invasion of the central nervous system after peripheral nerve infection, (2) direct involvement of the central nervous system through the olfactory bulb, (3) destruction of the blood-brain barrier (BBB) through lymphatic and hematogenous pathways, (4) severe destruction of the BBB caused by inflammatory responses to the virus, and (5) damage to the nervous system through the gut-brain axis (DosSantos et al, 2020;Kumar et al, 2020;Reza-Zaldivar et al, 2020;Dolatshahi et al, 2021). Because of the tropism of coronavirus to the gastrointestinal mucosa and the clinical manifestation of gastrointestinal diseases in patients with COVID-19, the gut-brain axis likely plays a vital role in SARS-CoV-2 neuroinvasion and comprehends an insight into its possible mechanisms.…”

Neurological update: COVID-19

“…Whereas the prior two hypothesized routes for CNS entry require infection of peripheral or cranial nerves, the haematogenous route entails either transcytosis across the vascular endothelium of the BBB, or a Trojan horselike reliance on infected host immune cells to bypass the BBB [42][43][44]. ACE2 is highly expressed on arterial and venous endothelial cells [14], and endothelial invasion by virus is well described [45], as is leukocyte infection [43], but neither of these explanations make the final leap to explaining passage into neurons themselves.…”