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
,
4
,
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
reported
2
and SARS‐CoV‐1 has been identified in neurones from tissues obtained from infected
patients.
9
The intranasal administration of SARS‐CoV‐1
10
or MERS‐COV
11
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‐CoV‐1 in the cerebrum, but not in cerebellum.
17
These two parts of the brain exhibit distinct ratios between neurones and neuroglia;
in the neocortex the number of non‐neuronal cells (most of which are represented by
neuroglia) is almost four times larger than the number of neurones, whereas in the
cerebellum neurones account for ~90% of all cells.
18
Upon infection and because of other forms of damage neuroglial cells become reactive,
representing the most classic neuropathological scenario of the ongoing neuroinflammation.
Therefore, it is possible that the SARS‐CoV‐2 infected brain regions triggers reactive
astrogliosis and activation of microglia.
This framework, as learned from studies of Tick‐borne encephalitis virus (TBEV) and
Zika virus (ZIKV), predicts a strong role of astrocytes and microglia in orchestrating
the nervous tissue response to neuroinfection and spread of the virus in the brain.
One of the fundamental events in the neuroinfection is the pathogen crossing of the
blood‐brain barrier (BBB). Astrocytes form the parenchymal portion of the BBB through
their endfeet, which extensively plaster (~98% of coverage) intracranial blood vessels.
In the grey mater astrocytes occupy separate territorial domains and integrate neural
elements with vasculature forming the neurovascular unit.
19
Both TBEV and ZIKV belong to the Flaviviridae family, and both viruses enter astrocytes
by endocytosis
20
,
21
thus instigating a neuroinfection. Internalization of TBEV into astrocytes is mediated
by the clathrin‐dependent endocytosis also known for several members of Flaviviridae
family including West Nile virus, Dengue virus, Hepatitis C virus and Bovine Viral
Diarrhoea virus.
21
Whether SARS‐Co‐V2 infects astroglial cells and enters astrocytes by endocytosis remains
to be studied, although the interneuronal transfer of another coronavirus HEV67 utilises
the clathrin‐dependent endocytotic/exocytotic pathway.
4
At least in the rodent brain, infection by TBEV has no detrimental effect on astroglial
viability and hence astrocytes likely represent a reservoir for TBEV from where further
infection and re‐infection can occur. Once within a cell, virus can traffic to different
compartments. In astroglia the TBEV uses the endosomal system for the spread within
the cytoplasm.
22
The spread of virus‐loaded vesicles exhibits directional mobility, which is driven
by protein motors carrying vesicles along the cytoskeletal elements, including microtubules,
actin and intermediate filaments. On the other hand, virus‐loaded vesicles may also
exhibit non‐directional mobility, characterized by randomness of free diffusion. As
a function of time, there is a series of events in virus‐infected cells, leading to
an increased number of TBEV particles per astrocytes, with a pronounced increase in
virus particle mobility.
22
Similar to the infiltration of TBEV, endocytosis was recently confirmed to be the
mechanism of ZIKV infection of astrocytes and microglia.
23
Among human cells, astrocytes were more susceptible to ZIKV infection than neurones,
released more progeny virus and tolerated higher virus loads than neurones.
20
The occurrence of the virus in the brain stem may affect chemosensing neural cells
associated with respiratory and cardiovascular regulation as well as respiratory centre
neurones thus damaging ventilatory lung function. Further support for the hypothesis
that the nasal route may contribute to the entry of the virus into the organism, including
the brain, is provided by clinical observations of an early and profound marked anosmia
in SARS‐CoV‐2 infected subjects (Ear, Nose and Throat surgery society, ENT UK; https://www.entuk.org/sites/default/files/files/LossofsenseofsmellasmarkerofCOVID.pdf).
Another fundamental aspect of the effect of SARS CoV2 infection and CNS is that this
infection triggers a substantial systemic inflammatory storm with a massive release
of cytokines, chemokines, and other inflammation signals with a subsequent significant
break of BBB, which instigates and amplifies the neuroinflammatory process. Numerous
preclinical and clinical studies consistently demonstrate that systemic inflammation,
regardless of its nature, be it bacterial, viral or toxic, compromises BBB, injures
glia limitans, activates Toll‐like receptors residing in microglia and astrocytes
and is associated with the innate immunity, ultimately promoting neuroinflammation
that may severely disturb brain homeostasis and cause neuronal death.
24
Therefore, the neuroinflammatory process associated with functional brain damage could
explain the clinical experience according to which even in patients who overcome pneumonia,
the onset or the progression of cognitive impairment associated with behavioural changes
is observed. Delirium and cognitive deficits and behavioural abnormalities are clearly
caused by a situation in which systemic inflammation associated with conditions of
prolonged hypoxia induces a persistent and uncontrolled neuroinflammation—responsible,
in turn, for damage to hippocampus and cortical areas associated with cognitive functions
and behavioural alterations.
25
Elderly patients recovering from pneumonia often exhibit delirium or deficits in attention
and memory that persist over time and require treatment, which is frequently remarkably
demanding. Delirium is commonly provoked by peripheral infection associated with systemic
inflammation. Elevated concentrations of serum pro‐interleukins and S100B, (recognized
as index of BBB disruption), have been observed during delirium in elderly patients.
26
Neuroinflammation appears as an almost obligatory component in neurodegenerative disorders
27
and has been implicated in psychiatric pathologies from acute psychosis to schizophrenia,
autism spectrum disorder, affective disorders to name but a few.
28
There is a strong association between systemic inflammation and depressive syndromes
with infections rising the risk of depressive episodes by ~60%.
28
In animal models, injections of cytokines instigates sickness behaviour
29
; which is very similar to a human “flu‐like syndrome” manifested by anhedonia, anorexia,
fever, fatigue, increased pain, sleep disturbances, and confusion. Furthermore, severe
respiratory failure accompanying COVID‐19 triggers long‐lasting hypoxia, which arguably
affects the brain and causes neurocognitive alterations.
To conclude: coronaviruses are neurotropic, and SARS‐CoV‐2 most likely is not an exception;
coronaviruses may enter the CNS through several routes, most notably through intranasal
inoculation and though peripheral nerves using trans‐synaptic pathways. Coronaviruses
can infect both neurones and neuroglia; neural cells express the entry protein ACE2,
although direct endocytotic infection (similar to those demonstrated for ZIKA and
TBEV viruses) cannot be excluded. Coronavirueses predominantly infect neurones in
the brain stem in the nuclei associated with cardio‐respiratory control; injuries
to these areas may exacerbate or even lead to respiratory failure. Direct CNS infection
together with systemic inflammation, which accompanies COVID‐19, compromises the blood
brain barrier and triggers a massive neuroinflammatory response manifested by reactive
astrogliosis and activation of microglia. Neuroinflammation together with prolonged
hypoxia may promote neuropsychiatric developments and cognitive impairments both acute
and chronic. The neurological and psychiatric aspects of the viral attack must therefore
be considered in designing the therapeutic strategies and for rehabilitation paradigms
aimed at victims of SARS‐CoV‐2.
CONFLICT OF INTEREST
No conflict of interest to declare.