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Cited by 367Long-Term Effects of COVID-19SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research Studies

Neuroinfection may contribute to pathophysiology and clinical manifestations of COVID‐19

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Steardo, Luca, Steardo, Luca, Zorec, Robert, Verkhratsky, Alexei·2020·Acta Physiologica
DOI 10.1111/apha.13473PMC PMC7228251
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Abstract

The new coronavirus, classified as severe acute respiratory syndrome (SARS)-CoV-2 that emerged in Hubei province in China, causes a new coronavirus disease, which was termed COVID-19 by WHO on 11 February 2020. COVID-19 claimed more than 65 000 lives around the world by 5th of April 2020. It is not the first coronavirus, which infects humans; the pathogenic viruses that cause human diseases (human coronaviruses, HCoV) include 6 other members designated as SARS-CoV, middle east respiratory syndrome (MERS)-CoV, HCoV-HKU1, HCoV-NL63, HCoV-OC43 and HCoV-229E. The clinical presentation is mainly manifested as malignant pneumonia; although many patients present neurological symptoms, such as vomiting, dizziness, headache and delirium.1 Human coronaviruses were first identified in the mid-1960s; they were named for the crown-like spikes on their surface. The SARS-CoV-2 virus belongs to β-coronavirus, which also include MERS-CoV, SARS-CoV-1, NCoV-OC43 and HCoV-HKU1. The primary target cells for SARS-CoV-2 are the epithelial cells of the respiratory and gastrointestinal tract, which contain angiotensin converting enzyme 2 (ACE2), that is utilized by the virus to enter the cell; it is, however, hard to believe that the penetration of the viral agent into the organism is limited only to these tissues.2 Clinical and pre-clinical data from studies with other coronaviruses suggest wider tissue invasiveness and an evident neurotropism, which may result in more complex clinical scenarios. Can the SARS-CoV-2 enter the central nervous system (CNS) and infect neural cells? And if yes, how the CNS damage contributes to pathophysiology of the COVID-19, to its signs, symptoms and progression as well as to its sequelae. In other words, if the SARS-CoV-2 virus had a significant neurotropism, could its presence in the CNS be pathophysiologically relevant? It has been demonstrated that coronaviruses, and especially β-coronaviruses to which the SARS-CoV-2 belongs, do not limit their presence to the respiratory tract and frequently invade the CNS. This propensity has been convincingly documented for the SARS-CoV, MERS-CoV and the coronavirus responsible for porcine haemagglutinating encephalomyelitis (HEV 67N).3-5 Previous findings demonstrate that ACE2 represents the key, but not the exclusive, site of entry of the virus into the cell. The ACE2 is expressed in the brain, being in particularly present in the brain stem and in the regions responsible for regulation of cardiovascular function including subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla; expression of ACE2 was found in both neurones and glia.6, 7 Non-ACE2 pathways for virus infection of neural cells also cannot be excluded; the marked penetration of coronavirus into the liver, an organ with lower levels of ACE 2 compared to the CNS, strongly supports the assumption that the cell entry routes can vary.8 Be this all as it may, the CNS infection with both SARS-CoV-1, MERS-CoV have been reported2 and SARS-CoV-1 has been identified in neurones from tissues obtained from infected patients.9 The intranasal administration of SARS-CoV-110 or MERS-COV11 resulted in the rapid invasion of viral particles into the brain, possibly through the olfactory bulb via trans-synaptic route. This pathway when virus enters peripheral nerves and spreads to the CNS through synaptic contacts has been well-documented for several viruses including CoVs.12 The brainstem, which hosts the respiratory neuronal circuit in the medulla, was severely infected with both types of viruses, which may contribute to degradation and failure of respiratory centres. When the nasal infecting charges were delivered in extremely low doses, only the CNS was colonized, with virus being absent in other tissues including lungs,11 corroborating the potent neurotropism of these coronarovirus strains. This testifies a viral property which cannot be ignored for a complete understanding of the impact of the β-coronaviruses on the human organism. Although direct evidence is currently lacking, the high identity between SARS-CoV-1 and SARS-CoV-2 suggests, that the latter viral strain could also infect the CNS, an ability clearly demonstrated by other members of the family to which they belong. The β-coronavirus NCoV-OC43, which causes upper respiratory tract disorder, has been found to infect neural cell lines as well as primary neurones in culture; it was also found to cause encephalitis associated with neuronal apoptosis and necrosis in mice.13 At least two cases of human encephalitis/encepahlomyelitis caused by NCoV-OC43 were also reported.14, 15 About 12% of children with clinical presentation of acute encephalitis hospitalised at the Children's Hospital of Chenzhou, China between May 2014 and April 2015 had anti-CoV antibodies in serum and in cerebrospinal fluid.16 It is of considerable interest that organ distribution studies have shown that the presence of SARS-C

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  • The cytokine storm theory proposes that the SARS-CoV-2 inflammatory response in the CNS is mediated by massive glial cell cytokine release, such as IL1b, IL-6, and IFN I-III.

    “Finally, the cytokine storm theory proposes that SARS-CoV-2 inflammatory response in the CNS is mediated by the massive glial cell cytokine release, such as IL1b, IL-6, and IFN I-III [168, 169].”

    From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [169]

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Authors
Steardo, L., Steardo, L., Zorec, R., & Verkhratsky, A.
Affiliations
  • University of Ljubljana (SI)
  • Ikerbasque (ES)
Corresponding author
Verkhratsky, Alexei
ORCID
Venue
Acta Physiologica
Publisher
Wiley
Published
2020-04-11
Volume
229
Issue
3
Pages
e13473-e13473
ISSN
  • 1748-1708 (ISSN-L)
  • 1748-1716
DOI
10.1111/apha.13473
PMC
PMC7228251
OpenAlex
W3013521296
Cited by
367
References
31
Citations by year
2026: 4 · 2025: 10 · 2024: 15 · 2023: 52 · 2022: 66 · 2021: 104 · 2020: 116
FWCI
36.56
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Acta Physiologica (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Repository of the University of Ljubljana (University of Ljubljana) (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
COVID-19 pandemic, central nervous system infection, neurotropism, central nervous system infiltration, SARS-CoV-2 pathophysiology, neurological symptoms, ACE2, betacoronaviruses, SARS-CoV-1, MERS-CoV, SARS-CoV-2 pathogenesis, clinical features
MeSH terms
Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Brain, Central Nervous System Infections, Humans, Peptidyl-Dipeptidase A, Neurons, Pneumonia, Viral, Coronavirus Infections, Pandemics

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