Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement, in the lethality of SARS‐CoV‐2 infection

Abstract

The outbreak of coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), has become a significant and urgent threat to the global health. This review provided strong support for CNS infection with SARS‐CoV‐2 and shed light on neurological mechanism underlying the lethality of SARS‐CoV‐2 infection. Among the published data, only 1.28% COVID‐19 patients who underwent cerebrospinal fluid (CSF) tests were positive to SARS‐CoV‐2 in CSF. However, this does not mean the absence of CNS infection in most COVID‐19 patients, because postmortem studies revealed that some patients with CNS infection showed negative results in CSF tests for SARS‐CoV‐2. Among 20 neuropathological studies reported so far, SARS‐CoV‐2 was detected in the brain of 58 cases in 9 studies, and three studies have provided sufficient details on the CNS infection in COVID‐19 patients. Almost all in vitro and in vivo experiments support the neuroinvasive potential of SARS‐CoV‐2. In infected animals, SARS‐CoV‐2 was found within neurons in different brain areas with a wide spectrum of neuropathology, consistent with the reported clinical symptoms in COVID‐19 patients. Several lines of evidence indicate that SARS‐CoV‐2 used hematopoietic route to enter the CNS. But more evidence supports the trans‐neuronal hypothesis. SARS‐CoV‐2 has been found to invade the brain via the olfactory, gustatory and trigeminal pathways, especially at the early stage of infection. Severe COVID‐19 patients with neurological deficits are at a higher risk of mortality, and only the infected animals showing neurological symptoms became dead, suggesting that neurological involvement may be one cause of death. This article is protected by copyright. All rights reserved.

Fatal neuroinvasion and SARS-CoV-2 tropism in K18-hACE2 mice is partially independent on hACE2 expression

“…To date, the precise mechanism(s) enabling neuroinvasion in the K18-hACE2 model is poorly understood (Bryche et al, 2020; DosSantos et al, 2020; Ellul et al, 2020; Liu et al, 2020; Solomon et al, 2020). Here, we determined that K18-hACE2 transgenic mice show a significant upregulation in the expression of ACE2 in the nasal cavity (particularly in the neuroepithelium) compared to wild-type C57BL/6J mice, in which ACE2 expression is undetectable by IHC.…”

“…Numerous comorbidities including hypertension, obesity and diabetes, among others, are affiliated with an increased risk of developing severe COVID-19 (Goyal et al, 2020; Simonnet et al, 2020; Tartof et al, 2020; Team, 2020; Tenforde et al, 2020). Furthermore, a proportion of infected patients develop poorly understood neurological signs and/or symptoms mostly associated with the loss of smell and taste (anosmia and ageusia), headache, dizziness, encephalopathy (delirium), and ischemic injury (stroke), among other uncommon symptoms (DosSantos et al, 2020; Eliezer et al, 2020; Ellul et al, 2020; Goyal et al, 2020; Lee et al, 2020; Liu et al, 2020; Solomon et al, 2020; Walker et al, 2020; Wang et al, 2020b). Recently, SARS-CoV-2 RNA and antigen has been reported in the brain of COVID-19 patients and the olfactory mucosa postulated as a port of entry (Meinhardt et al, 2020).…”

Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease

“…Many brain regions and several cell types have been reported to express ACE2 or other proteins implicated in COVID-19 pathogenesis 36,61,79–81 but, aside from the olfactory bulb, much attention has been focused on the brainstem as it was reportedly affected in the 2003 SARS-CoV epidemic and in animal models of viral infection, possibly indicative of entry through the cranial nerves and in particular through respiratory and gastrointestinal tract epithelium and thence the vagus nerve 1,82,83 . Human coronavirus experimental models have shown selective brain localization as well as axonal transport and hematogenous CNS entry 24,25,82,84–86 .…”

Sars-Cov-2 infection related inflammatory and demyelinating disease; a brief case series

“…Up to date, some of the human coronaviruses (HCoV) strains have been shown to have neurotropic effect as they can spread from the respiratory tract to the central nervous system (CNS) ( Desforges et al, 2019 ). When it comes to the novel coronavirus, there is little evidence to date to suggest that SARS-CoV2 might invade neural cells ( Liu et al, 2020 ). In this case series, we suggest that the virus might play a role in the clinical onset of the inflammatory demyelinating diseases.…”