Received: 10 November 2020 | Revised: 7 December 2020 | Accepted: 8 December 2020

DOI: 10.1002/jmv.26720

REVIEW

Cellular mechanisms underlying neurological/

neuropsychiatric manifestations of COVID‐19

Brittany Bodnar1,2,3 | Kena Patel1,2,4 | Wenzhe Ho1 | Jin Jun Luo5 |

Wenhui Hu1,2,3

1
Department of Pathology and Laboratory
Medicine, Lewis Katz School of Medicine, Abstract
Temple University, Philadelphia,
Patients with severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection
Pennsylvania, USA
2
Center for Metabolic Disease Research,
manifest mainly respiratory symptoms. However, clinical observations frequently iden-
Lewis Katz School of Medicine, Temple tified neurological symptoms and neuropsychiatric disorders related to COVID‐19
University, Philadelphia, Pennsylvania, USA
(Neuro‐SARS2). Accumulated robust evidence indicates that Neuro‐SARS2 may play an
3
Biomedical Sciences Graduate Program,
Lewis Katz School of Medicine, Temple important role in aggravating the disease severity and mortality. Understanding the
University, Philadelphia, Pennsylvania, USA neuropathogenesis and cellular mechanisms underlying Neuro‐SARS2 is crucial for both
4
Undergraduate Research Program, College basic research and clinical practice to establish effective strategies for early detection/
of Science and Technology, Temple
University, Philadelphia, Pennsylvania, USA diagnosis, prevention, and treatment. In this review, we comprehensively examine cur-
5
Department of Neurology and Department rent evidence of SARS‐CoV‐2 infection in various neural cells including neurons, micro-
of Pharmacology, Lewis Katz School of
glia/macrophages, astrocytes, pericytes/endothelial cells, ependymocytes/choroid
Medicine, Temple University, Philadelphia,
Pennsylvania, USA epithelial cells, and neural stem/progenitor cells. Although significant progress has been
made in studying Neuro‐SARS2, much remains to be learned about the neuroinvasive
Correspondence
Wenhui Hu, Center for Metabolic Disease
routes (transneuronal and hematogenous) of the virus and the cellular/molecular
Research, Department of Pathology and mechanisms underlying the development/progression of this disease. Future and ongoing
Laboratory Medicine, Temple University
Lewis Katz School of Medicine, 3500 N Broad
studies require the establishment of more clinically relevant and suitable neural cell
St, Philadelphia, PA 19140, USA. models using human induced pluripotent stem cells, brain organoids, and postmortem
Email: whu@temple.edu
specimens.

Funding information
KEYWORDS
NIH, Grant/Award Numbers: R01AI145034,
brain organoids, COVID‐19, iPS cells, neural cells, neuroinvasion, neurology, neuropsychiatry,
R01DA050505
neurovirulence, SARS‐CoV‐2

1 | INTRODUCTION
The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2)
virus has caused a global pandemic affecting 218 countries and
territories with 51,791,296 confirmed cases and 1,278,460 con-
firmed deaths, as of November 10, 2020 (www.worldometers.info/
coronavirus), and large numbers of new cases still occur daily. The
unprecedented scale of the pandemic continues to push the bound-
aries of scientific research and development as the community pro-
ceeds to further understand the virus and its complexity involving
multiple organ systems with varying severities. The most common
and predominant presentations of illness are respiratory symptoms.

Abbreviations: ACE2, angiotensin‐converting enzyme‐2; BBB, blood–brain barrier; BCSFB, blood‐CSF barrier; CNS, central nervous system; CO, cerebral organoid; CoV, coronavirus;
COVID‐19, coronavirus disease 2019; CSF, cerebrospinal fluid; CVO, circumventricular organ; DRG, dorsal root ganglion; iPSC, induced pluripotent stem cell; K18, human cytokeratin 18;
MERS, Middle East respiratory syndrome; MERS‐CoV, Middle East respiratory syndrome coronavirus; Neuro‐SARS, neurological/neuropsychiatric manifestation of severe acute respiratory
syndrome; NPC, neural progenitor cell; NSC, neural stem cell; PNS, peripheral nervous system; RT‐PCR, reverse‐transcription polymerase chain reaction; SARS, severe acute respiratory
syndrome; SARS‐CoV, severe acute respiratory syndrome coronavirus; TMPRSS2, transmembrane protease serine 2; ZIKV, Zika virus.

J Med Virol. 2021;93:1983–1998. wileyonlinelibrary.com/journal/jmv © 2020 Wiley Periodicals LLC | 1983

1984 | BODNAR
However, there are increasing reports of neurological and neu-
ropsychiatric symptoms.1–8 Such symptoms may be nonspecific, such
as somatoform disorders including muscle soreness, dizziness, head-
ache, anxiety, sleep disturbances, depression, fatigue, anger/stress,
loneliness, stigmatization; or specific, such as central nervous system
(CNS) disorders including stroke, seizures, encephalitis, ataxia, and
myelitis; peripheral nervous system (PNS) disorders including loss of
smell and taste (anosmia/hyposmia and ageusia/dysgeusia), Guillain‐
Barré syndrome and Miller Fisher syndrome; or psychiatric and neu-
ropsychiatric syndromes including major depressive disorder, bipolar
disorder, obsessive‐compulsive disorder and posttraumatic stress
disorder. The exact mechanisms of SARS‐CoV‐2 underlying neurolo-
gical/neuropsychiatric dysfunctions are not fully understood but seem
to be due to a combination of potentially direct viral infection, or
indirect systemic disease complication plus para/post‐infectious in-
flammation in the nervous system. Notably, knowledge of the long‐
term effects of SARS‐CoV‐2 on the nervous system in surviving
COVID‐19 patients is virtually absent.
In this review, we focus on the current understanding of cellular
mechanisms underlying COVID‐19 neurological/neuropsychiatric
pathogenesis and symptoms. Accumulated evidence has shown that
SARS‐CoV‐2 may directly infect various neural cells. Additionally,
systemic immune activation and chronic neuroinflammation may also
contribute to neurological dysfunctions. Although severe neurological
complications seem to be rare, the global scale of the pandemic can
amount to a large number of cases in the long‐term as symptoms and
latent effects of the virus continue to manifest, potentially leaving
patients with prolonged existing neurological and/or neuropsychiatric
disturbances.7,8 Presumably, neurological and neuropsychiatric man-
ifestations in surviving COVID‐19 patients may have equal, if not
more significant, adverse consequences when compared to pulmon-
ary manifestations. Understanding the cellular mechanisms will pave
the way for basic research directions and clinical therapeutic stra-
tegies. For better clarity and understanding, we tentatively assign
SARS1 for the original 2003 SARS caused by SARS‐CoV‐1 and SARS2
for the 2019 COVID caused by SARS‐CoV‐2, while SARS defines
both SARS1 and SARS2, and SARS‐CoV represents SARS‐CoV‐1 and
SARS‐CoV‐2.
2 | CL I NI CA L EVI D E N C E OF SAR S ‐ COV ‐ 2
I N F E C T I O N IN TH E N E R V O U S SY S T E M
Neurologic and neuropsychiatric dysfunctions in SARS2 patients
have recently been well discussed.1–6,9 However, many questions
remain to be clarified, particularly if these neurologic/psychiatric
disturbances are caused by direct infection of SARS‐CoV‐2 to the
brain or the downstream consequences via indirect mechanisms
caused by SARS‐CoV‐2 systematically. The previous clinical findings
of the brains from patients infected with SARS‐CoV‐1 have sug-
gested that these SARS‐CoVs are able to invade the brain. Sub-
sequent clinical reports have documented both CNS and PNS
involvement including stroke, seizures, smell loss, Guillain‐Barré
ET AL.
syndrome, and myopathies (manifested as rhabdomyolysis).10
Autopsies from several SARS1 patients revealed the presence of
SARS‐CoV‐1 in the brain, primarily in the cytoplasm of neurons in the
cortex and hypothalamus.11 Additionally, SARS‐CoV‐1 could be de-
tected in the cerebrospinal fluid (CSF) of SARS1 patients who were
experiencing seizures.10 Similarly, neurological complications were
reported in some patients with MERS, including peripheral neuro-
pathies, encephalopathies, intracerebral hemorrhage, stroke, sei-
zures, and confusion.12 However, there is no confirmatory evidence
from post‐mortem or CSF viral detection studies to support
MERS‐CoV directly infecting the brain.
In SARS2 cases, SARS‐CoV‐2 has been detected by reverse‐
transcription polymerase chain reaction (RT‐PCR) assay in the CSF of
numerous patients with various neurological symptoms13–17 al-
though many anecdotal clinical reports showed a negative test for
SARS‐CoV‐2 by RT‐PCR assays of CSF samples.18 The reason why no
viral load was detectable in the CSF of the majority of SARS2 pa-
tients with an active neurological condition remains unclear. This
discrepancy could be due to the differences in sensitivity of RT‐PCR
assays, the stages of infection, and the timing when the CSF sample
is manipulated and the assay is performed, or the clearance of
SARS‐CoV‐2 from the CSF. Nonetheless, detection of SARS‐CoV‐2
by RT‐PCR in CSF from patients with active neurological symptoms
has provided undeniable evidence that SARS‐CoV‐2 could invade the
nervous system. Undoubtedly, more studies are needed to secure
convincible evidence.
A case series study of 18 post‐mortem SARS2 patients with
various neurological symptoms has shown evidence of acute hypoxic‐
ischemic damages in the brains of all patients, including neuronal
loss.19 Of these patients, the virus was detected by RT‐PCR in five
brains. SARS‐CoV‐2 spike (S) protein was detected in cortical neu-
rons and endothelial cells in SARS2 brain samples20 but not the viral
nucleocapsid (N) protein by immunohistochemical analyses.19
Other neuropathological case studies have found histological
evidence of vascular etiologies, encephalitis (both global and
brainstem‐specific) and/or meningitis, demyelination, and other en-
cephalopathies.21,22 Post‐mortem analysis using transmission electron
microscopy and RT‐PCR assay in a SARS2 patient with Parkinson's
disease revealed the presence of SARS‐CoV‐2 in neurons and capillary
endothelial cells in the frontal lobe.23 However, the question remains
whether the outcome neuropathology resulted from direct infection
or a downstream event following a systemic infection; or whether the
lack of evidence of vital direct infection was an outcome of the low
sensitivity of the detection threshold in methodologies. New tech-
nologies such as RNAscope have been utilized to detect SARS‐CoV‐2
RNA in cultured cells24 and lung specimens of SARS2 patients, and are
expected to validate the existence of SARS‐CoV‐2 in brain tissues.
Digital droplet PCR, viral outgrowth assay, and single‐cell RNA se-
quencing of brain samples from SARS2 patients may also help to va-
lidate the neurotropism of SARS‐CoV‐2. Further multilabeled
immunohistochemical analyses are needed to better understand the
cellular distribution and mechanisms of SARS‐CoV‐2 in the nervous
system.
BODNAR ET AL.
In summary, accumulated evidence from clinical studies has
shown a variety of neurological and neuropsychiatric manifestations
in SARS2 patients (Table 1). However, more convincible evidence for
direct viral infection to the nervous system remains to be found in
addition to the indirect contribution of systemic immune/in-
flammatory responses after SARS‐CoV‐2 infection.46 The availability
of the advanced new technologies for neuropathogenic studies on
human brain specimen are expected to continuously provide in‐
depth findings of SARS‐CoV‐2 infection in the nervous system.
3 | THE N EU ROPATHOGENIC MODELING
F OR SA R S 2
Due to the limited sources of human brain specimen from SARS2
patients, various models have been developed to explore the neu-
rovirulent infection of SARS‐CoV‐2 in various types of neural cells
and recapitulate the neuropathogenesis and neurological manifes-
tation as well as their correlations with viral neuroinvasion (Table 2).
3.1 | Preclinical animal models
Angiotensin‐converting enzyme‐2 (ACE2) has been well recognized to
serve as the major receptor for SARS‐CoV‐2 to gain entry into host
cells.68 The homology conservation and the expression patterns of ACE2
69
in various species have been identified. Therefore, numerous non‐
rodent species have been tested as natural animal models for SARS2,
including monkey, ferret, hamster, cat, bat, and pig.70 Cynomolgus ma-
caques infected with SARS‐CoV‐2 exhibit virus shedding and replication
in lung tissues and certain pathological changes, but no clinical signs,71
while another study showed moderate clinical symptoms in rhesus ma-
caques infected with SARS‐CoV‐2.72 Thus, nonhuman primate models
may be useful for further preclinical tests; however, monkey models, in
general, fail to manifest clinical illness and are very expensive and in-
convenient. Mouse models are more practical and feasible for elucidating
virus pathogenicity and therapeutic targets. However, both SARS‐CoVs
exhibit a poor cellular tropism in wild‐type mice due to significant species
difference in ACE2 sequence and function. Thus, various types of human
ACE2 (hACE2)‐expressing mouse models have been established for
SARS‐CoV‐2 infection (Table 2). Interestingly, only hACE2 mouse models
among the currently available SARS2 animal models fully recapitulated
SARS2 clinical scenarios, particularly the severity and mortality of the
illness. The successfully established hACE2‐transgenic mouse model with
high susceptibility to both SARS‐CoV‐1 and SARS‐CoV‐2 infection
provided a useful tool in SARS‐CoVs studies,47,52,54,55 particularly
K18‐hACE2 transgenic mice, in which hACE2 expression is driven by the
epithelial cell‐specific promoter human cytokeratin 18 (K18) and is cap-
able of recapitulating many features of SARS‐CoV‐2 infections,47,48,52
47,48
even better than the other hACE2‐expressing mouse models.
Although numerous reports on SARS2 animal models are avail-
able, the understanding of neuroinvasive pathogenesis and resultant
neurological changes caused by the virus remains limited. In SARS2
| 1985
animal studies, the virus is delivered intranasally, which may readily
infect the brain via the olfactory nervous system. The brain cellular
expression pattern of ACE2 in these animal models may address the
susceptibility of brain tissues/cells to SARS‐CoV‐2. SARS‐CoV‐2
RNAs are detected in the brain of hACE2 mice after intranasal
inoculation.49,54,55
3.2 | Human brain organoid models
To get the most clinically relevant data for whether and how
SARS‐CoV‐2 may infect the human brain, it is important to use ma-
terials from humans. The simplest and most direct approach to test
human cellular susceptibility to SARS‐CoV‐2 is to utilize immortalized
human neural cell lines or primary neural cells. SARS‐CoV‐2 can
moderately infect and replicate in the human glioblastoma cell line
U251.73 Primary olfactory sensory neurons of human4 and hamsters74
are highly susceptible to SARS‐CoV‐2 infection. However, another
study did not detect any presence of SARS‐CoV‐2 in primary olfactory
neurons in hamsters but did identify viral infection in a large pro-
portion of the supporting sustentacular cells.75 In cultured human
neural stem cells (NSC)/neural progenitor cells (NPCs), ACE2,
TMPRSS2, cathepsin L, and furin were readily detected and cells
were highly susceptible to infection with SARS‐CoV‐2,61 but not
SARS‐CoV‐1.61 Human primary astrocytes are rarely (0.18%) infected
by SARS‐CoV‐2.58 Other human primary neural cells have not yet
been examined for their susceptibility to SARS‐CoV‐2 infection.
Fortunately, the rapidly evolving technology surrounding stem
cell culture has allowed for the generation of human‐induced plur-
ipotent stem cells (iPSCs) that can be differentiated into virtually any
cell lineage. This has led to the generation of pure human neural cells
such as NSCs/NPCs, neurons, astrocytes, microglia, oligoden-
drocytes, endothelial cells, etc. Human iPSC‐derived neurons,
particularly dopaminergic neurons, are highly susceptible to
S‐pseudotyped SARS‐CoV‐2 infection, but iPSC‐derived microglia
and macrophages are moderately infected by S‐pseudovirions.59 In
contrast, another report showed that iPSC‐derived neurons and as-
trocytes were sparsely infected, and microglia had no infection;
however, interestingly, the choroid plexus epithelial cells underwent
robust infection by live SARS‐CoV‐2 virus.58 The inconsistent reports
in neural cell viral susceptibility may result from variable differ-
entiation protocols, neural cell maturity, and virus infection dosage.
Three‐dimensional tissue cultures known as organoids contain
multiple cell types and recapitulate tissue structures and develop-
ment. Cerebral organoids (COs) have been used to model several
neurodevelopmental and neuropathological disorders as they accu-
rately resemble the molecular, cellular, and structural features of the
developing brain (Figure 1A). COs can be readily infected with
neurotropic viruses and develop phenotypes similar to that seen
clinically, as has been shown in several models studying the Zika
virus (ZIKV).76
As it is very difficult to obtain clinical brain samples from patients
who died of SARS2, the COs are an attractive live human brain model for
1986 | BODNAR ET AL.

T A B L E 1 Clinical features of
Manifestation type Symptom/feature Percentage Reference
neurological and neuropsychiatric
25–27
symptoms in SARS2 patients (percentages General neurological Any nervous symptoms 36.4%–82.3%
derived from the clinical studies with >100 symptoms Headache 6.5%–70.3% 25–34

patients; the others noted the case Muscle pain (myalgia) 22%–62.5% 25–34

numbers) Dizziness 8%–29.7% 26–28,30,34

28,30,32,34
Fatigue 50%–69.6%
26,27,35–37
Seizures <1%
26,27,30,38
Impaired/disordered 4.3%–9%
consciousness
26
Rhabdomyolysis 3.5%
25–28,32,33,39
Sensory impairments Anosmia/hyposmia 5.1%–70.2%
25–28,32,33,39
Ageusia/dysgeusia 5.6%–54.2%
25,27,32
Vision impairment 1.4%–7.4%
26,27,36,37
Neuropathies Peripheral neuropathy 0.4%–8.9%
36,37,40
Gullian–Barre syndrome and 23 cases
variants
27
Nerve pain 2.3%
25,26
Focal weakness and/or motor 0.6%–2.5%
deficit
26,36,37
Encephalopathies Encephalopathy (undefined) 7.2%–31.8%
25,29,35,37,38
Confusion/disorientation/altered 2.0%–27.9%
mental state
17,41
Acute necrotizing 3 cases
encephalopathy (ANE)
21,36
Leukoencephalopathy 2 cases
30
Hypoxic encephalopathy 9%
22,36
Inflammations Acute demyelinating 10 cases
encephalomyelitis (ADEM)
36
Myelitis (CNS) 3 cases
26,36,37,42
Encephalitis 15 cases
42
Lymphocytic meningitis 6 cases
21,27,35–37,42,43
Acute cerebrovascular Ischemic stroke 1.4%–5.0%
disease Intracerebral hemorrhage 25 cases 21,26,35,37,42,43

38
Neuropsychiatric Depression 32.6%
presentations Anxiety 35.7% 38

25,38
Sleep disorders/insomnia 37.2%–41.9%
38
Anger/stress/irritability 3.9%
37,38
Psychosis 0.8%–4.4%
25
Behavioral disorder 2.0%
(not specified)
38
Frequent recall of traumatic 30.4%
memories
37
Cognitive disorder 0.5%
19,30
Neuropathologic Acute hypoxic‐ischemic damage
features Astrogliosis 22,44,45

19,45
Microgliosis
22
Demyelination
17,19,21,22,42,44,45
Neuronal cell loss/injury
45
Cytotoxic T‐cell infiltration
22
Macrophage infiltration
 BODNAR
ET AL.

TABLE 2 Experimental models for SARS2 neuropathogenesis

Model Description Model characteristics References

3 5 20,47–53
In vivo Mouse Models Transgenic Human ACE2 expression driven by the epithelial High susceptibility to SARS‐CoV‐2 infection (2 × 10 –1 × 10 plague
K18‐hACE2 mice cell‐specific K18 promoter formation unit) and best recapitulation of several SARS2 clinical
features; Several studies also report presence of viral RNA and/or
histopathological findings in the brains of some mice20,47–51
54
Transgenic Human ACE2 expression driven by the lung ciliated Susceptibility to SARS‐CoV‐2 infection and presentation of interstitial
HFH4‐hACE2 mice epithelial cell‐specific HFH4/FOXJ1 promoter pneumonia; High viral RNA levels were detected in the brain of a
portion of mice and was highly correlated with increased mortality
55
Transgenic CRISPR/Cas9 edited knock‐in mice that express human Human ACE2 replaces mouse Ace2 expression; high susceptibility to
hACE2 mice ACE2 under the mouse genomic Ace2 promoter SARS‐CoV‐2 infection, with particularly high viral RNA levels found
in the brain
47,56,57
Adenovirus delivery of Human ACE2 packaged in adenoviral particles under the Human ACE2 expressing cells show susceptibility to SARS‐CoV‐2
hACE2 CMV promoter and delivered to wild‐type mice for infection, with high viral titers in lung tissues; Mice develop some
exogenous expression of hACE2 pathologies but do not display severe SARS2 features
20,58–62
In vitro human Monolayer neural cell Human iPSC‐derived neural cell cultures patterned into Monolayer cultures of mature neurons58‐60 of various subtypes
iPSC‐derived culture cultures specific cell types (e.g., dopaminergic, cortical, etc.), NSCs/NPCs20,61,62 and glial cell
models cultures58,59 including microglia and astrocytes; Susceptibility to
SARS‐CoV‐2 infection varies by cell type
20,60,61,63–65
Cerebral organoids 3D cerebral organoids generated from human iPSCs Mature organoids present as a heterogenous 3D structure consisting of
multiple neural cell types, including neurons, NSCs/NPCs, and glial
cells; Susceptible to SARS‐CoV‐2 infection to various extent
58
Region‐specific 3D cerebral organoids generated from human iPSCs that Organoids of hippocampal, midbrain, hypothalamic, and forebrain
cerebral organoids are patterned to specific regional lineages subtypes with heterogenous mixture of neural cells; Varied
susceptibility to SARS‐CoV‐2 infection
58,66
Choroid plexus 3D cerebral organoids generated from human iPSCs High susceptibility to SARS‐CoV‐2 infection; SARS‐CoV‐2 infection
organoids primarily composed of choroid plexus epithelial cells leads to transcriptional dysregulation and impaired barrier function
67
Blood vessel organoids 3D organoid structures derived from human iPSCs High susceptibility to SARS‐CoV‐2 infection that can be inhibited in an
composed of vascular networks of endothelial cells ACE2‐dependent manner
|
1987
1988 | BODNAR ET AL.

F I G U R E 1 Human brain organoids to model SARS‐CoV‐2 infection. A, Example timeline of an experiment to generate COs with SARS‐CoV‐2
infection. Human fibroblasts or PBMCs are reprogrammed to generate iPSCs, which are then grown in 3D suspension culture as EBs. After
neural induction, COs are embedded in Matrigel to promote formation of neuroepithelial lobes and then transferred to spinning culture, using
an orbital shaker or similar method. At around one month, microglia begin to mature in microglia‐containing COs. By around 50–60 days,
astrocytes can be detected in COs. At this point, COs are in a state of growth and neural cell maturation; this is typically the time point where
COs are infected with SARS‐CoV‐2 for experiments. B, Examples of different types of COs. After pre‐patterning to a neuroectodermal fate
using dual SMAD inhibition, EBs can be induced into region‐specific organoids by adding different patterning factors. Several studies have used
this technique to examine the effect of SARS‐CoV‐2 infection on different brain regions, particularly the choroid plexus. CO, cerebral organoid;
EB, embryoid body; iPSC, induced pluripotent stem cell; MPC, microglia progenitor cell; NSC/NPC, neural stem/progenitor cell; OPC,
oligodendrocyte progenitor cell; PBMC, peripheral blood mononuclear cell; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2

studying the impact of SARS‐CoV‐2 infection on the CNS. Utilizing CO
models, several labs have demonstrated that the virus can readily infect
20,58,59,61,63,64,66
and replicate within COs derived from human iPSCs.
mojority of these studies showed that SARS‐CoV‐2 preferentially in-
fected neurons and that viral particles were primarily localized to the
soma, sometimes extending into neurites and axons. This infection of
COs was further confirmed in two studies using electron microscopy,
showing viral particles in neurons and viral budding in the endoplasmic
reticulum.20,61 An additional study using a SARS‐CoV‐2 pseudovirus in-
The stead of a living virus also found that neurons of COs readily uptake viral
particles, with a similar expression pattern.60 Although these findings
provide little clue about how SARS‐CoV‐2 crosses the BBB and enters
the brain, they demonstrate that iPSC‐derived human brain organoids
are susceptible to the SARS‐CoV‐2 infection.
BODNAR ET AL.
4 | N E U R A L C E L L S U S C EP T I B I L I T Y T O
SARS ‐C O V‐ 2
SARS‐CoV‐2 is primed by proteases such as transmembrane protease
serine 2 (TMPRSS2) and requires expression of its receptor angiotensin‐
converting enzyme‐2 (ACE2) to gain entry into host cells.68 However,
several other receptors have been identified that serve as potential re-
ceptors or co‐receptors for SARS‐CoV‐2 infection such as neuropilin‐1,77
CD147,78,79 CD26,80–82 CD133,82 CD209,83 furin,61,79 and cadherin‐
17.82 Therefore, studying the expression of ACE2 and other potential
receptors throughout the body helps bring understanding to cell sus-
ceptibility to SARS‐CoV‐2 infection. Earlier studies found ACE2 mRNA
expression nearly ubiquitous but its protein expression more restricted,
with high levels found in the heart, kidneys, lung epithelium, small in-
testine, and vascular endothelium.84 In the brain, neural cells include
neurons, astrocytes, oligodendrocytes, microglia/macrophages,
NSCs/NPCs, ependymal cells, pericytes, endothelial cells, and various
types of immune cells (Table 3). These neural cells also exhibit an en-
ormous diversity in their subtypes, sizes, shapes, regional locations, and
functions (Figure 1B). The expression pattern of ACE2 and other po-
tential receptors in various neural cells remains to be determined and
their susceptibility to SARS‐CoV‐2 may vary with physiological and pa-
thological conditions. Exploration of SARS‐CoV‐2 neurotropism and cel-
lular localization is important in elucidating SARS2 neuropathogenesis
and developing therapeutic and prophylactic countermeasures.
4.1 | Neurons
Both in vitro and in vivo studies have demonstrated the neuronal sus-
ceptibility to SARS‐CoV‐2, although the infection efficiency varied with
neuronal subtypes, regional difference, and entry receptor expression
patterns. Database mining showed weak expression of hACE2 in human
brain cortical neurons but strong expression of CD147 and neuropilin‐1.
Experiments using RT‐PCR, immunostaining, and immunoblotting
validated hACE2 expression in human neurons to various extents. The
expression of entry receptors destinates the neuronal infectivity of
SARS‐CoV‐2. The human glioblastoma cell line U25173 and primary ol-
4
factory sensory neurons are susceptible to SARS‐CoV‐2 infection. In
hamsters, one report identified high infection of primary olfactory neu-
rons, but another study found viral infection only in sustentacular cells
instead of olfactory neurons (Figure 2A).75 In mice, pervasive expression
of Ace2 protein in olfactory epithelial sustentacular cells and olfactory
bulb pericytes but not olfactory sensory neurons was detected by im-
munohistochemistry, suggesting that olfactory bulb neurons are likely
not a primary site of infection, but that vascular pericytes may be sen-
94
sitive to SARS‐CoV‐2. Interestingly, SARS‐CoV‐2 infected COs at Day
60 at a significantly higher rate than at Day 15, suggesting that the virus
prefers infecting more mature neural cells64 (Figure 1). Neurons in the
hypothalamus and with dopaminergic properties are highly susceptible to
SARS‐CoV‐2, indicating its potential affinity to some neuroanatomic
structures underlying pathogenesis for clinical Neuro‐SARS symptoms.95
The S protein‐immunoreactivity is detected in brain neurons of
| 1989
K18‐hACE2 mice after SARS‐CoV‐2 infection49 by intranasal delivery,
suggesting the possibility that SARS‐CoV‐2 live virus can infect brain
neurons via the intranasal route.
4.2 | Microglia/macrophages
Microglia in the brain play a critical role in neurodevelopment, neural
innate immunity, and neuroinflammation. Microglia, like macrophages,
may predominantly contribute to the inflammatory response during
Neuro‐SARS2,93 as significant activation of microglia and neuronophagia
exists in the brainstem (pons, medulla oblongata), and olfactory bulb of
SARS2 patients.85 Whether SARS‐CoV‐2 can infect and replicate in mi-
croglia remain elusive. In iPSC‐derived microglia, one study showed no
infection of live SARS‐CoV‐2 virus, but another study demonstrated
moderate susceptibility to S‐pseudovirions.59 SARS‐CoV‐2 has been
shown to infect monocytes and macrophages, resulting in host im-
munoparalysis.96 In human macrophages from lymph nodes and lung,
SARS‐CoV‐2 was detected by immunohistochemistry and electron mi-
croscopy.97 Whether infected macrophages infiltrate the brain, serving as
a hijacking mechanism for SARS‐CoV‐2, remains to be determined.
4.3 | Pericytes and endothelium cells (EC)
The blood–brain barrier (BBB) functions to protect the brain against
harmful invasion such as viruses. The BBB permeability is exquisitely
regulated by the neurovascular unit formed by highly specialized
endothelial cells, pericytes, astrocytes, and others (Figure 2C). Early
studies with immunohistochemistry showed that ACE2 expression
was limited to vascular endothelial cells in the human brain.84 In-
terestingly, a recent study demonstrated that ACE2 in the brain is
not expressed in the vascular endothelial cells but instead in
pericytes.89 Several single‐cell RNA‐seq studies have identified a
high level of ACE2 in pericytes.98 Pericytes wrap themselves around
the vascular endothelium and play a critical role in maintaining
vascular integrity. However, it is unlikely that the virus would be able
to cross the BBB by passing from the blood to pericytes unless
the vascular endothelium itself was damaged in the first place
(Figure 2C), whether it be from pre‐existing conditions, direct viral
infection, or post‐infectious immune response. There has been direct
evidence for SARS‐CoV‐2 infection of vascular endothelial cells and
endothelialitis reported in clinical cases.99 This evidence is further
corroborated by a recent study in which SARS‐CoV‐2 was able to
readily infect engineered human blood vessel organoids, which could
be reduced using clinical‐grade soluble ACE2.67 iPSC‐derived
endothelial cells are also susceptible to SARS‐CoV‐2 infection.59
The severity of vasculopathy in the brain correlates with the sever
ity of SARS2 neurological symptoms such as stroke or mental
alterations.100 A clinical case report identified profound pericyte
apoptosis in the lungs of SARS2 patients, which might be the initial
trigger of micro‐vasculopathy.101 Direct evidence for SARS‐CoV‐2
infection in brain pericytes and the sequela is still lacking.
 1990
|

TABLE 3 Neural cell susceptibility to SARS‐CoV‐2 infection

Cell type Receptor expression Susceptibility to infection Consequences of infection in vitro Consequences of Infection in vivo

Neurons Varied expression of ACE2
(subtype and region specific)
Varying reports of susceptibility
Increased cell death20,58,63,64; impaired
synaptogenesis20,61,63; Tau mislocalization64
Evidence of direct SARS‐CoV2 infection in neurons of K18‐
hACE2 and hACE2 transgenic mice20,49,50,55 and select
clinical SARS2 cases20,23; neuronal
injury,17,19,21,22,42,44,85–87 neuronal necrosis and/or
neuronophagia19,22,45,86,88 detected in clinical SARS2
cases

Microglia Inconsistent reports Inconsistent reports Not available due to low susceptibility to SARS‐ Reactive microglia/microgliosis detected in SARS‐CoV‐2
CoV‐2 infection infected K18‐hACE2 transgenic mice49 and clinical
SARS2 cases,19,45,85–88 but no evidence of direct
infection of microglia; presence of microglial nodules in
select SARS2 cases19,45,86,88

Pericytes/ High expression of ACE284,89,90 High susceptibility67 High levels of viral replication and shedding67 Vasculitis and other cerebrovascular etiologies detected in
Endothelial and TMPRSS2 K18‐hACE2 transgenic mice20,49,50; acute
Cells cerebrovascular injuries in numerous clinical SARS2
cases (see Table 1)

Choroid Plexus High expression of ACE2 and High susceptibility58,66 Increased cell death, downregulation of genes One clinical case report of direct SARS‐CoV2 infection in
Cells TMPRSS258,66,90–92 related to BCSFB integrity and upregulation of endothelial cells of the choroid plexus and tanycytes of
inflammatory genes58; Impaired barrier the median emminence92
function66

NSCs/NPCs Moderate expression of ACE2; Conflicting reports of low to Increased cell death20,61,63 No evidence available
expression of TMPRSS2, furin, moderate
and cathepsin L61 susceptibility20,61,63,66

Astrocytes Weak to little ACE2 expression91 Low susceptibility49,58,66,93 Not available due to low susceptibility to SARS‐ Reactive astrocytes/astrocytosis detected in SARS‐CoV‐2
CoV‐2 infection infected K18‐hACE2 transgenic mice49,50 and clinical
SARS2 cases17,22,44,45 but no evidence of direct
infection of astrocytes
BODNAR
ET AL.
BODNAR ET AL.
| 1991

F I G U R E 2 Diagrams for some potential routes of SARS‐CoV‐2 neuroinvasion. There are two primary routes by which SARS‐CoV‐2 may
invade the brain: (1) transneuronally or (2) hematogenously. Potential transneuronal routes include nasally via the olfactory system, orally via
the gustatory/trigeminal nerves, spinally via the dorsal root ganglia (either via sensory receptors in the skin or in the gut), or through the enteric
nervous system via the vagus nerve. Potential hematogenous routes can occur with an intact BBB via the choroid plexus or CVOs, or with
an impaired BBB via damaged endothelial cells. A, SARS‐CoV‐2 may invade the brain via the olfactory system. Viral particles enter the olfactory
epithelium after passage through the nasal cavity. Within the olfactory epithelium, SARS‐CoV‐2 can create a reservoir within support cells,
such as sustentacular cells. The virus may enter the olfactory bulb transneuronally, via axons of olfactory receptor neurons, or by alternative
routes, such as infection of vascular pericytes (not pictured) or entry into the CSF in the subarachnoid space. Basal cells of the olfactory
epithelium and olfactory ensheathing cells within the lamina propria and subarachnoid space are also susceptible to SARS‐CoV‐2 infection.
B, SARS‐CoV‐2 may invade the brain by crossing the BBB or blood–CSF barrier. Viral particles travel through the blood and exit through
fenestrated capillaries within the choroid plexus. SARS‐CoV‐2 may infect choroid plexus epithelial cells and be shed into the CSF, from which
they could cross into brain parenchyma. Additionally, viral particles may pass through fenestrated capillaries of CVOs directly into brain
parenchyma and/or CSF. C, SARS‐CoV‐2 may invade the brain by crossing the BBB. Viral particles travel through the blood and exit into
the brain parenchyma by infecting or passing through damaged endothelial cells and/or their surrounding pericytes or hijacking by infected
immune cells (not pictured). Within the parenchyma, SARS‐CoV‐2 may directly infect neural cells or elicit an immune/inflammatory response.
Schematic created using BioRender.com. BBB, blood–brain barrier; CSF, cerebrospinal fluid; CVO, circumventricular organ; SARS‐CoV‐2,
severe acute respiratory syndrome coronavirus‐2

4.4 | Choroid plexus epithelial cells and
ependymal cells
The choroid plexus is a complex network of epithelial cells sur-
rounding capillaries in the ventricles of the brain and is the primary
region of CSF production. The epithelial cells of the choroid plexus
also have a unique role as serving as the major barrier between the
blood and CSF (termed the blood–CSF‐barrier or BCSFB) (Figure 2B).
The BCSFB acts similarly to the BBB as a selectively permeable
barrier for transport to and from the brain but likewise is also sus-
ceptible to pathogen invasion. One study looking at SARS‐CoV‐2
infectability in region‐specific COs (including hippocampal, hy-
pothalamic, midbrain, and cortical) (Figure 1B) found that choroid
plexus epithelial cells expressed in hippocampal organoids were
susceptible to SARS‐CoV‐2 viral infection at a much higher rate than
that of neurons and other neural cell subtypes.58 This led the authors
1992 | BODNAR
to generate choroid plexus specific organoids, which displayed very
high rates of infection even at low viral titer, strongly suggesting that
SARS‐CoV‐2 may be able to invade the brain by infecting choroid
plexus epithelial cells in humans. Another study validated the high
susceptibility of the choroid plexus to SARS‐CoV‐2 S‐pseudovirus
and live virus in iPSC‐derived brain organoids and demonstrated the
leakage of BCSFB due to SARS‐CoV‐2‐induced choroid plexus epi-
thelial damages.66 This possibility is further supported by recent
evidence finding high expression of ACE2 and TMPRSS2 in the
choroid plexus of both humans and mice.66,90,91
The ependymal cells are unique neuroepithelial cells lining the brain
ventricles and are critical for CSF generation and regulation. Their basal
membranes contact astrocyte endfeet via tentacle‐like extensions.
SARS‐CoV‐2 has been detected in the CSF of SARS2
patients.13–17,102,103 If SARS‐CoV‐2 in the CSF can infect ependymal
cells and render neuroinvasion remains to be determined (Figure 2B).
Given ependymal cells have weak or no expression of ACE291
and TMPRSS2,91 they may express other viral entry receptors for
SARS‐CoV‐2, or may allow neuroinvasion under pathological conditions.
4.5 | NSCs/NPCs
Neurogenesis occurs throughout life in both animals and humans. NSCs
are self‐renewing, multipotent, and long‐lived cells that generate the
main cell types of the nervous system. NSCs represent a small population
of quiescent and slowly dividing cells, whereas their intermediate NPCs
are a large population of amplifying, rapidly dividing cells. NSCs/NPCs are
susceptible to various virus infections such as ZIKV, Dengue virus, CMV,
76,104 62
etc. ACE2 is highly expressed in human iPSC‐derived NSCs/NPCs ;
thus, three studies validated infection of SARS‐CoV‐2 in these cells.58,61
However, another study did not detect ACE2 expression or SARS‐CoV‐2
infection in NSCs/NPCs.66 NSCs share properties with pericytes, epen-
dymal cells, and tanycytes. In circumventricular organs (CVOs), NSCs
may have direct contact with circulating pathogens. The functional states
and cell fate decisions of NSCs/NPCs after SARS‐CoV‐2 infection war-
rant further investigation.
4.6 | Astrocytes
As astrocytes are the most abundant cell type in the CNS, their role
in neural virulence has been well studied for different viruses. The
endfeet of astrocytes play a key role in the formation and function of
the BBB. However, SARS‐CoV‐2 infection efficiency is very low or
absent in human primary astrocytes,58,66,93 which may be due to high
heterogeneity of astrocyte subtypes as well as weak/rare expression
91
of ACE2 and TMPRSS2. As is the case with HIV infection in as-
trocytes, a minority of GFAP‐positive cells infected by SARS‐CoV‐2
may represent NSCs. A better understanding of the similarity and
diversity of SARS‐CoV‐2 infection between NSCs and astrocytes may
provide new therapeutic routes for Neuro‐SARS2.
ET AL.
5 | POTENTIAL NEUROINVASIVE ROUTES
FO R SARS ‐ COV ‐2 IN F EC T IO N
Neurological symptoms and neuropsychiatric disorders in SARS2
patients have been extensively reported and evaluated in numerous
review papers.1–6,9 The viral entry receptor expression and infection
susceptibility of neural cells strongly support the preliminary con-
clusion that SARS‐CoV‐2 can effectively infect various types of
neural cells in the human brain and cause neurological/neu-
ropsychiatric pathogenesis and symptoms. However, the routes for
SARS‐CoV‐2 neuroinvasive infection remain to be determined. The
possibility of the following potential routes is explored based on
currently available literature (Figure 2).
5.1 | Retrograde/anterograde axonal transport
and transneuronal invasion
Neurotropic viruses may invade neurons via virion trafficking in a
retrograde or/and anterograde manner by interacting with neuronal
cytoskeletal proteins. After neuronal infection, the virions may be
released and transneuronally spread to neighboring or presynaptic
neurons. Many RNA viruses have been shown to invade the CNS via
this transneuronal pathway including SARS‐CoV‐1, thus SARS‐CoV‐2
is extrapolated to follow similar transneuronal routes to infect the
nervous system.
5.1.1 | Intranasal epithelium and olfactory nervous
system
One of the most plausible proposed routes of neuroinvasion of
SARS‐CoV‐2 is via the olfactory system. Invasion by this route would
involve the virus infecting cells of the olfactory epithelium, poten-
tially establishing a viral reservoir (Figure 2A).4,105 This is because (1)
olfactory epithelial cells have high ACE2 and TMPRSS2 expression90;
(2) several clinical studies identified SARS‐CoV‐2 infection in the
olfactory nerve system,19 including MRI hyperintensity in the olfac-
tory bulb of SARS2 patient106; (3) a large majority of SARS2 patients
present loss of smell/taste28,39,107,108; and (4) intranasal delivery of
SARS‐CoV‐2 effectively induces brain infection in animal models.50
Once cells in the olfactory epithelium are infected, the virus could
either travel transneuronally via axons of olfactory receptor neurons
or by non‐neuronal cells up to the olfactory bulb.105 However, it is
still less clear if SARS‐CoV‐2 can infect neuronal cells within the
olfactory epithelium to invade the brain via the olfactory bulb, as
olfactory receptor neurons express relatively low levels of ACE2.109
If the olfactory bulb and/or olfactory nerves are infected by
SARS‐CoV‐2, it may provide the mechanisms for the widely reported
loss of smell and/or taste in SARS2 patients.28,39,107,108,110 Alter-
natively, an impaired sense of smell may be the result of an immune
response in the olfactory epithelium, as these cells also co‐express
BODNAR ET AL.
high levels of innate immune response genes and olfactory epithelial
biopsies from SARS2 patients show significantly increased levels of
pro‐inflammatory cytokines.111
5.1.2 | Oral health and gustatory/trigeminal
nervous system
Oral health plays an important role in the severity of SARS2 devel-
opment. Oral bacterial infection may increase the risk of SARS‐CoV‐2
infection. The majority of SARS2 patients present taste disturbances
such as ageusia, dysgeusia, xerostomia.110,112 In some cases this may
present as a prodromal symptom or as the sole manifestation of
113
SARS2, particularly at the early stage. A large cohort study that
enrolled >2 million participants concluded that the loss of smell and
taste is more predictive of SARS‐CoV‐2 infection than all other
symptoms, including fatigue, fever, or cough. Similar to olfactory
neuronal terminals, the gustatory and trigeminal nerve endings may
be highly susceptible to SARS‐CoV‐2 infection, especially at the early
stage of infection (Figure 2).112 Understanding the mechanism of
these neuroinvasions will provide a better strategy for the early di-
agnosis, prevention, and treatment of SARS2 patients, particularly in
regard to neurological manifestations.
5.1.3 | Skin and the peripheral nervous system
The human dorsal root ganglion (DRG) neurons express high levels of
ACE2 at both mRNA and protein levels.114 Database mining showed
a broad expression of entry receptors in human DRG at the lumbar
and thoracic levels. In a subset of nociceptive neurons, ACE2 is co-
expressed with MRGPRD (Mas‐related G‐protein coupled receptor
member D), a polymodal nociceptive receptor on the nerve endings
at the outermost layers of skin and luminal organs. SARS‐CoV‐2 can
115
survive on the skin for 9 hours. Thus, SARS‐CoV‐2 may infect
human nociceptors, causing not only peripheral pain but also neu-
roinvasion into the CNS via DRG sensory neurons (Figure 2). How-
ever, direct evidence for DRG infection is still lacking.
5.1.4 | Gut infection and enteric nervous system
In addition to respiratory symptoms, gastrointestinal symptoms are
also paramount in SARS2 patients due to the abundant expression of
116
ACE2 and other potential entry receptors in mature enterocytes.
Presence of SARS‐CoV‐2 viral RNA can be identified in the stool of
117
SARS2 patients. The intrinsic enteric nervous system is enriched
with neurons and glial cells and exquisitely innervates mucosal epi-
thelial cells. Its location makes the enteric nerve endings be readily
exposed to the invading viruses. Notably, a high level of ACE2 and
TMPRSS2 expression has been identified in a large number of enteric
neurons and enteric glia cells.91 Thus, the enteric nervous system is
assumed to be susceptible to SARS‐CoV‐2 infection. The virus could
| 1993
infect enteric neurons and travel along the well‐established gut‐brain
axis such as the vagus or splanchnic nerve routing into the CNS
(Figure 2). Several viruses have been shown to take the gut‐brain
transneuronal pathway to infect the CNS, such as herpes, varicella‐
zoster virus, and influenza.118 Additionally, infection in the enteric
glial cells could induce various degrees of inflammatory responses,
which may aggravate systemic and neurological symptoms.
5.2 | Hematogenous invasion to the nervous
system
5.2.1 | SARS‐CoV‐2 hematogenous dissemination
to circumventricular organ (CVO) and choroid plexus
under physiological condition
Another potential route of SARS‐CoV‐2 infection into the brain could
be via circumventricular organs (CVOs) and/or choroid plexus, where
the BBB is absent, particularly at the early stage of SARS2 wherein
the BBB and BCSFB remain intact elsewhere (Figure 2B).93 The BBB
under physiological conditions functions to prevent harmful patho-
gens from entering the brain. However, CVOs have no BBB struc-
ture, allowing the circulating pathogens, along with nutrients and
metabolites, cytokines and hormones to freely travel through and
out from the brain.119 Specific CVOs include the median eminence,
subfornical organ, and organum vasculosum lamina terminalis
(around the third ventricles at the mid‐level hypothalamus), as well
as the area postrema in the brain stem. Direct imaging to track the
SARS‐CoV‐2 reporter virus passing through the CVO into the brain
in human brain organoids or animal models is warranted.
The theory of the choroid plexus serving as an invasion route for
neurotropic viruses was recently highlighted in a study showing that
ZIKV can infect pericytes and cross the BCSFB via the choroid plexus
in mice.120 Interestingly, ZIKV's presence in the CSF and infection of
the choroid plexus preceded infection in the rest of the brain,
which could be attenuated by neutralizing the virus in the CSF. If
SARS‐CoV‐2 utilized a similar neuroinvasion mechanism, it could
explain the inconsistency in CSF detection of the virus. SARS‐CoV‐2
may enter the brain via the CSF before infection of CNS neurons and
then the CSF viral levels may decrease over time as it is cleared by
the immune system; however, this could be when neurological
symptoms begin to manifest as the virus spreads in the brain. Both
CVOs and the choroid plexus are characterized by fenestrated and
highly permeable capillaries (Figure 2B).93 SARS‐CoV‐2 in the CSF
may infect ependymal cells and subsequently infect CVOs then
spread to neural cells.
5.2.2 | Transendothelial invasion via damaged BBB
under pathological condition
The BBB is formed by the highly specialized endothelial cells, peri-
cytes, and astrocytes, and is regulated by the neurovascular unit.
1994 | BODNAR
BBB could be damaged by virus infection of any cell components of
BBB or the post‐infectious inflammatory responses. The SARS‐CoV‐2
virus in the blood may directly infect brain endothelial cells and
transendothelially disseminate virus into brain parenchyma via the
damaged BBB, which could be aggravated by viral infection and in-
flammatory storm (Figure 2C).121
5.2.3 | Hijacking (trajectory) route via infected
immune cells
Several neurotropic viruses such as HIV and Western Nile virus have
been shown to enter brain through a “Trojan horse” mechanism, in
which infected immune cells traffic across the permeabilized BBB
and spread the hidden viruses to neurons and glial cells.122
SARS‐CoVs have been shown to infect monocytes/macrophages,
lymphocytes, and leukocytes.96,123 Thus, SARS‐CoV‐2 is likely able to
121
traffic across the BBB and BCSFB to infect neural cells.
6 | NEURAL CELL CONSEQUENCE AFTER
SARS ‐C O V‐ 2 IN F E C TIO N
While elucidating the mechanisms of how SARS‐CoV‐2 may enter the
brain is highly important to our understanding of neurological/neu-
ropsychiatric manifestations of SARS2, it is equally critical to understand
the cellular consequences that result from the virus once in the brain,
such as neural cell survival/death, proliferation, migration, virus produc-
tion, viral spread, etc. Several studies report increased neuronal cell
death in COs after SARS‐CoV‐2 infection as determined by TUNNEL
staining and caspase‐3 immunostaining.20,58,63,64 Histopathological ex-
aminations of human brain autopsy specimens have characterized sig-
19
nificant neuronal damage. NSCs/NPCs also experience significant cell
death.20,61,63 Although less data is available for glial cells, such as astro-
cytes and microglia, if infected, they may produce various extents of
immune/inflammatory responses or neuroprotective responses. Intrigu-
ingly, cells infected with SARS‐CoV‐2 may promote the death of unin-
fected neighboring cells.20,58 Robust syncytial formation of infected cells
found in the lung of SARS2 patients124 may also occur to neural cells,
being a source neuropathogenesis in the brain.
Transcriptomics analysis identified large scale transcriptional dys-
regulation, particularly in metabolic genes and cytokine storm genes as
well as genes related to the hypoxia response in SARS‐CoV‐2‐infected
cells or choroid plexus organoids,20,58,63,64 confirming the local hypoxic
environment in neurons surrounding SARS‐CoV‐2 infected cells via
HIF1α expression. The upregulation of vascular remodeling genes and
the downregulation of genes related to CSF secretory function as well
as cell junction genes suggest a potentially impaired function of the
BCSFB and BBB.
Significantly decreased expression of vGLUT1, an excitatory pre‐
synapse marker, has been identified in human brain organoids, sug-
gesting impaired synaptogenesis in SARS‐CoV‐2 infected cells.20,61,63
Another study identified Tau mislocalization in the neuronal soma of
ET AL.
SARS‐CoV‐2‐infected mature neurons as opposed to the typical lo-
calization within axons of normal neurons.64 Further investigation
showed that the phospho‐Tau mislocalization is specific to
pT231Tau, which correlated with a fraction of cells that also ex-
pressed caspase‐3. Thus, SARS‐CoV‐2 infection results in aberrant
pT231Tau phosphorylation, which may trigger programmed cell
death pathways. Intriguingly, the neuronal apoptosis induced by
SARS‐CoV‐2 infection appears dependent on Type II interferon re-
sponse (IFNγ), but not Type I interferon response (IFNα/β).20,58,63,64
7 | CONCLUSIONS A ND FUTURE
DIRECTIONS
Accumulated evidence from clinical observations and laboratory
studies helps to understand the neuropathogenesis underlying
SARS‐CoV‐2 infection‐causing various neurological and neu-
ropsychiatric conditions in SARS2 patients. It remains to be de-
termined whether SARS‐CoV‐2 directly or indirectly induces
neurological/psychiatric damages. Studies have shown that many of
SARS2 patients with an active neurological symptom had no detect-
able virus in the CSF. In addition, no virus could be recovered from the
brain tissues of patients who died of SARS2. These observations
suggest the possibility that indirect effects such as inflammation in-
duced by SARS‐Cov‐2 infection contribute to the neurological/neu-
ropsychiatric manifestations. However, failure to detect the virus may
be due, at least partly, to the low sensitivity of the assays, stages of
infection, and timing when the samples were examined. Notably,
studies from different groups reported the significant differences in
SARS‐CoV‐2 infection of various neural cells, which may be re-
sponsible for the conflicting data reported. Hopefully, with the avail-
ability of more advanced technologies such as RNAscope,84,94 digital
droplet PCR,85,93,95 viral outgrowth assay,96,97 single‐cell RNA se-
quencing,89,98 and multilabeled immunohistochemical analysis as well
as better in vivo and in vitro models such as preclinical animals, human
iPSCs, and human brain organoids for various neural cells, we will be
able to determine the mechanisms for SARS‐Cov‐2 infection‐caused
neurological injury, which is crucial in developing strategies for
treatment of SARS2 patients with the neurological/neuropsychiatric
manifestations. Although several new studies using brain organoids
offer strong and straightforward evidence for the neuroinvasive effect
on different neural cells with particularly high susceptibility of choroid
plexus epithelial cells, there are still limitations of current brain
organoid technology to recapitulate clinical patients, including
immaturity of neural cells, unclear dose of neurovirulent infection in
vivo, and lack of additional cell types such as microglia, pericytes,
endothelial cells, oligodendrocytes, and immune cells.58 Given that the
SARS2 pandemic remains raging and seasonal resurgence is impend-
ing, more extended efforts and investigation into Neuro‐SARS2
mechanisms remain urgently needed. Long‐term follow‐up for poten-
tial neurological/neuropsychiatric manifestations as well as the de-
velopment of novel prophylactic and therapeutic treatments for
Neuro‐SARS2 are equally critical.
BODNAR ET AL.
A C K N O W L E D GM E N T
This study was supported by the National Institute of Health
1R01DA050505‐01 (WZH and WHH) and 1R01AI145034 (WHH).
The content of this review article is solely the responsibility of the
authors and does not necessarily represent the official views of the
National Institutes of Health. All authors have read the journal's
authorship agreement and policy on disclosure of potential conflicts
of interest. No English writing service was sought for this manuscript.
C O NF L IC T O F IN T E R ES T S
The authors declare that there are no conflict of interests.
AUTHOR CONTRIBUTIONS
Brittany Bodnar and Wenhui Hu: Conceptualization and design,
literature search, drafting, editing, and critical revision. Jin Jun Luo
and Wenzhe Ho: reviewing, editing, and critical revision. Kena Patel:
Literature search, table preparation, and drafting. All approved the
final version of the manuscript.
DATA AV AILA BILITY STATEMENT
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
ORCID
Brittany Bodnar http://orcid.org/0000-0003-0467-5219
Wenhui Hu http://orcid.org/0000-0001-8152-6116
R EF E RE N C E S
1. Assari S. COVID‐19 Pandemic and neurological disease: a critical
review of the existing literature. Hosp Pract Res. 2020;5:81‐86.
2. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of
COVID‐19. Lancet Neurol. 2020;19:767‐783.
3. Kumar M, Thakur AK. Neurological manifestations and comorbid-
ity associated with COVID‐19: an overview. Neurol Sci. 2020;41:
3409‐3418.
4. Cooper KW, Brann DH, Farruggia MC, et al. COVID‐19 and the
chemical senses: supporting players take center stage. Neuron.
2020;107:219‐233.
5. Iadecola C, Anrather J, Kamel H. Effects of COVID‐19 on the
nervous system. Cell. 2020;183:16‐27 e1.
6. Oliveira R, Sotero FD, Teodoro T. NeuroCOVID: critical review of
neuropsychiatric manifestations of SARS‐CoV‐2 infection. Ir J Med
Sci. 2020. https://doi.org/10.1007/s11845-020-02367-4
7. Sinanovic O, Muftic M, Sinanovic S. COVID‐19 pandemia: neu-
ropsychiatric comorbidity and consequences. Psychiatr Danub.
2020;32:236‐244.
8. Roy D, Ghosh R, Dubey S, Dubey MJ, Benito‐León J, Kanti Ray B.
Neurological and neuropsychiatric impacts of COVID‐19 pan-
demic. Can J Neurol Sci. 2020:1‐16.
9. Nalleballe K, Reddy Onteddu S, Sharma R, et al. Spectrum of
neuropsychiatric manifestations in COVID‐19. Brain Behav Immun.
2020;88:71‐74.
10. Lau K‐K, Yu W‐C, Chu C‐M, Lau ST, Sheng B, Yuen KY. Possible
Central nervous system infection by SARScoronavirus. Emerging
Infect Dis. 2004;10:342‐344.
11. Gu J, Gong E, Zhang B, et al. Multiple organ infection and the
pathogenesis of SARS. J Exp Med. 2005;202:415‐424.
| 1995
12. Kim J‐E, Heo J‐H, Kim H, et al. Neurological complications during
treatment of Middle East respiratory syndrome. J Clin Neurol.
2017;13:227‐233.
13. Andriuta D, Roger P‐A, Thibault W, et al. COVID‐19 encephalo-
pathy: detection of antibodies against SARS‐CoV‐2 in CSF. J Neurol.
2020;267:2810‐2811.
14. Cebrián J, Gonzalez‐Martinez A, García‐Blanco MJ, et al. Headache
and impaired consciousness level associated with SARS‐CoV‐2 in
CSF. Neurology. 2020;95:266‐268.
15. Fadakar N, Ghaemmaghami S, Masoompour SM, et al. A first case of
acute cerebellitis associated with coronavirus disease (COVID‐19): a
case report and literature review. Cerebellum. 2020;19:911‐914.
16. Kremer S, Lersy F, de Sèze J, et al. Brain MRI findings in severe
COVID‐19: a retrospective observational study. Radiology. 2020;
297:E242‐E251.
17. Virhammar J, Kumlien E, Fällmar D, et al. Acute necrotizing en-
cephalopathy with SARS‐CoV‐2 RNA confirmed in cerebrospinal
fluid. Neurology. 2020;95:445‐449.
18. Bellon M, Schweblin C, Lambeng N, et al. Cerebrospinal fluid fea-
tures in SARS‐CoV‐2 RT‐PCR positive patients. Clin Infect Dis.
2020. https://doi.org/10.1093/cid/ciaa1165
19. Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropatholo-
gical features of COVID‐19. N Engl J Med. 2020;383:989‐992.
20. Song E, Zhang C, Israelow B, et al. Neuroinvasion of SARS‐CoV‐2 in
human and mouse brain. bioRxiv. 2020. https://doi.org/10.1101/
2020.06.25.169946
21. Hernández‐Fernández F, Sandoval Valencia H, Barbella‐Aponte RA,
et al. Cerebrovascular disease in patients with COVID‐19: neuroima-
ging, histological and clinical description. Brain. 2020;143:3089‐3103.
22. Reichard RR, Kashani KB, Boire NA, Constantopoulos E, Guo Y,
Lucchinetti CF. Neuropathology of COVID‐19: a spectrum of vas-
cular and acute disseminated encephalomyelitis (ADEM)‐like pa-
thology. Acta Neuropathol. 2020;140:1‐6.
23. Paniz‐Mondolfi A, Bryce C, Grimes Z, et al. Central nervous system
involvement by severe acute respiratory syndrome coronavirus‐2
(SARS‐CoV‐2). J Med Virol. 2020;92:699‐702.
24. Carossino M, Ip HS, Richt JA, et al. Detection of SARS‐CoV‐2 by
RNAscope((R)) in situ hybridization and immunohistochemistry
techniques. Arch Virol. 2020;165:2373‐2377.
25. Kacem I, Gharbi A, Harizi C, et al. Characteristics, onset, and
evolution of neurological symptoms in patients with COVID‐19.
Neurol Sci. 2020. https://doi.org/10.1007/s10072-020-04866-9
26. Liotta EM, Batra A, Clark JR, et al. Frequent neurologic manifes-
tations and encephalopathy‐associated morbidity in COVID‐19
patients. Ann Clin Transl Neurol. 2020;7:2221‐2230.
27. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospi-
talized patients with coronavirus disease 2019 in Wuhan, China.
JAMA Neurology. 2020;77:683.
28. Spinato G, Fabbris C, Polesel J, et al. Alterations in smell or taste in
mildly symptomatic outpatients with SARS‐CoV‐2 infection. JAMA.
2020;323:2089‐2091.
29. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical char-
acteristics of 99 cases of 2019 novel coronavirus pneumonia in
Wuhan, China: a descriptive study. Lancet. 2020;395:507‐513.
30. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 de-
ceased patients with coronavirus disease 2019: retrospective
study. BMJ. 2020;368:m1091.
31. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with
2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497‐506.
32. Klopfenstein T, Kadiane‐Oussou NJ, Toko L, et al. Features of
anosmia in COVID‐19. Med Mal Infect. 2020;50:436‐439.
33. Lechien JR, Chiesa‐Estomba CM, Place S, et al. Clinical and epidemio-
logical characteristics of 1420 European patients with mild‐to‐
moderate coronavirus disease 2019. J Intern Med. 2020;288:335‐344.
1996 | BODNAR
34. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospi-
talized patients with 2019 novel coronavirus–infected pneumonia
in Wuhan, China. JAMA. 2020;323:1061.
35. Benussi A, Pilotto A, Premi E, et al. Clinical characteristics and
outcomes of inpatients with neurologic disease and COVID‐19 in
Brescia, Lombardy, Italy. Neurology. 2020;95:e910‐e920.
36. Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum
of COVID‐19 neurology: clinical, radiological and laboratory find-
ings. Brain. 2020;143:3104‐3120.
37. Varatharaj A, Thomas N, Ellul MA, et al. Neurological and
neuropsychiatric complications of COVID‐19 in 153 patients: a
UK‐wide surveillance study. Lancet Psychiatry. 2020;7:875‐882.
38. Rogers JP, Chesney E, Oliver D, et al. Psychiatric and neu-
ropsychiatric presentations associated with severe coronavirus
infections: a systematic review and meta‐analysis with comparison
to the COVID‐19 pandemic. Lancet Psychiatry. 2020;7:611‐627.
39. Giacomelli A, Pezzati L, Conti F, et al. Self‐reported olfactory and
taste disorders in patients with severe acute respiratory cor-
onavirus 2 infection: a cross‐sectional study. Clin Infect Dis. 2020;
71:889‐890.
40. Dalakas MC. Guillain‐Barré syndrome: the first documented
COVID‐19–triggered autoimmune neurologic disease. Neurology
Neuroimmun Neuroinflam. 2020;7:e781.
41. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B.
COVID‐19‐associated acute hemorrhagic necrotizing encephalo-
pathy: imaging features. Radiology. 2020;296:E119‐E120.
42. Weyhern CH, von Kaufmann I, Neff F, Kremer M. Early evidence of
pronounced brain involvement in fatal COVID‐19 outcomes.
Lancet. 2020;395:e109e.
43. Li Y, Li M, Wang M, et al. Acute cerebrovascular disease following
COVID‐19: a single center, retrospective, observational study.
Stroke Vasc Neurol. 2020;5:279‐284.
44. Kanberg N, Ashton NJ, Andersson L‐M, et al. Neurochemical evi-
dence of astrocytic and neuronal injury commonly found in
COVID‐19. Neurology. 2020;95:e1754‐e1759.
45. Matschke J, Lütgehetmann M, Hagel C, et al. Neuropathology of
patients with COVID‐19 in Germany: a post‐mortem case series.
Lancet Neurol. 2020;19:919‐929.
46. Abdelaziz OS, Waffa Z. Neuropathogenic human coronaviruses:
a review. Rev Med Virol. 2020;30:e2118.
47. Rathnasinghe R, Strohmeier S, Amanat F, et al. Comparison of
transgenic and adenovirus hACE2 mouse models for SARS‐CoV‐2
infection. Emerg Microbes Infect. 2020;9:2433‐2445.
48. Winkler ES, Bailey AL, Kafai NM, et al. SARS‐CoV‐2 infection of
human ACE2‐transgenic mice causes severe lung inflammation and
impaired function. Nature Immunol. 2020;21:1‐9.
49. Golden JW, Cline CR, Zeng X, et al. Human angiotensin‐converting
enzyme 2 transgenic mice infected with SARS‐CoV‐2 develop se-
vere and fatal respiratory disease. JCI Insight. 2020;5(19):e142032.
https://doi.org/10.1172/jci.insight.142032
50. Yinda CK, Port JR, Bushmaker T, et al. K18‐hACE2 mice develop
respiratory disease resembling severe COVID‐19. bioRxiv. 2020.
https://doi.org/10.1101/2020.08.11.246314
51. Zheng J, Wong LYR, Li K, et al. COVID‐19 treatments and patho-
genesis including anosmia in K18‐hACE2 mice. Nature. 2020.
https://doi.org/10.1038/s41586-020-2943-z
52. Moreau GB, Burgess SL, Sturek JM, Donlan AN, Petri WA, Mann BJ.
Evaluation of K18‐hACE2 mice as a model of SARS‐CoV‐2 infection.
Am J Trop Med Hyg. 2020;103:1215‐1219.
53. Bao L, Deng W, Huang B, et al. The pathogenicity of SARS‐CoV‐2 in
hACE2 transgenic mice. Nature. 2020;583:830‐833.
54. Jiang R‐D, Liu M‐Q, Chen Y, et al. Pathogenesis of SARS‐CoV‐2 in
transgenic mice expressing human angiotensin‐converting enzyme
2. Cell. 2020;182:50‐58.
ET AL.
55. Sun SH, Chen Q, Gu HJ, et al. A mouse model of SARS‐CoV‐2
infection and pathogenesis. Cell Host Microbe. 2020;28:124‐133.
56. Hassan AO, Case JB, Winkler ES, et al. A SARS‐CoV‐2 infection
model in mice demonstrates protection by neutralizing antibodies.
Cell. 2020;182:744‐753.
57. Sun J, Zhuang Z, Zheng J, et al. Generation of a broadly useful
model for COVID‐19 pathogenesis, vaccination, and treatment.
Cell. 2020;182:734‐43.e5.
58. Jacob F, Pather SR, Huang W‐K, et al. Human pluripotent stem cell‐
derived neural cells and brain organoids reveal SARS‐CoV‐2 neu-
rotropism predominates in choroid plexus epithelium. Cell Stem
Cell. 2020;27(6):937‐950.
59. Yang L, Han Y, Nilsson‐Payant BE, et al. A human pluripotent stem cell‐
based platform to study SARS‐CoV‐2 tropism and model virus infection
in human cells and organoids. Cell Stem Cell. 2020;27:125‐136.e7.
60. Yi SA, Nam KH, Yun J, et al. Infection of brain organoids and 2D
cortical neurons with SARS‐CoV‐2 pseudovirus. Viruses. 2020;12:
1004.
61. Zhang BZ, Chu H, Han S, et al. SARS‐CoV‐2 infects human neural
progenitor cells and brain organoids. Cell Res. 2020;30:928‐931.
62. Kase Y, Okano H. Expression of ACE2 and a viral virulence‐
regulating factor CCN family member 1 in human iPSC‐derived
neural cells: implications for COVID‐19‐related CNS disorders.
Inflamm Regen. 2020;40:32.
63. Mesci P, Macia A, Saleh A, et al. Sofosbuvir protects human brain
organoids against SARS‐CoV‐2. bioRxiv. 2020. https://doi.org/10.
1101/2020.05.30.125856
64. Ramani A, Müller L, Ostermann PN, et al. SARS‐CoV‐2 targets
neurons of 3D human brain organoids. EMBO J. 2020;39:e106230.
65. Bullen CK, Bullen K. Infectability of human brainsphere neurons
suggests neurotropism of SARS‐CoV‐2. ALTEX. 2020;37(3):665–671.
66. Pellegrini L, Albecka A, Mallery DL, et al. SARS‐CoV‐2 infects the
brain choroid plexus and disrupts the blood‐CSF barrier in human
brain organoids. Cell Stem Cell. 2020;27:951‐961.e5.
67. Monteil V, Kwon H, Prado P, et al. Inhibition of SARS‐CoV‐2 in-
fections in engineered human tissues using clinical‐grade soluble
human ACE2. Cell. 2020;181:905‐913.
68. Hoffmann M, Kleine‐Weber H, Schroeder S, et al. SARS‐CoV‐2 cell
entry depends on ACE2 and TMPRSS2 and is blocked by a clini-
cally proven protease inhibitor. Cell. 2020;181(2):271‐280.
69. Alexander MR, Schoeder CT, Brown JA, et al. Predicting suscept-
ibility to SARS‐CoV‐2 infection based on structural differences in
ACE2 across species. FASEB J. 2020;34:15946‐15960.
70. Cleary SJ, Pitchford SC, Amison RT, et al. Animal models of me-
chanisms of SARS‐CoV‐2 infection and COVID‐19 pathology. Br
J Pharmacol. 2020;177:4851‐4865.
71. Rockx B, Kuiken T, Herfst S, et al. Comparative pathogenesis of
COVID‐19, MERS, and SARS in a nonhuman primate model.
Science. 2020;368:1012‐1015.
72. Munster VJ, Feldmann F, Williamson BN, et al. Respiratory disease
in rhesus macaques inoculated with SARS‐CoV‐2. Nature. 2020;
585:268‐272.
73. Chu H, Chan JFW, Yuen TTT, et al. Comparative tropism, replica-
tion kinetics, and cell damage profiling of SARS‐CoV‐2 and
SARS‐CoV with implications for clinical manifestations, transmis-
sibility, and laboratory studies of COVID‐19: an observational
study. Lancet Microbe. 2020;1(1):e14‐e23.
74. Zhang AJ, Lee ACY, Chu H, et al. SARS‐CoV‐2 infects and damages
the mature and immature olfactory sensory neurons of hamsters.
Clin Infect Dis. 2020. https://doi.org/10.1093/cid/ciaa995
75. Bryche B, St Albin A, Murri S, et al. Massive transient damage of
the olfactory epithelium associated with infection of sustentacular
cells by SARS‐CoV‐2 in golden Syrian hamsters. Brain Behav Immun.
2020;89:579‐586.
BODNAR ET AL.
76. Qian X, Nguyen HN, Song MM, et al. Brain‐region‐specific orga-
noids using mini‐bioreactors for modeling ZIKV exposure. Cell.
2016;165:1238‐1254.
77. Cantuti‐Castelvetri L, Ojha R, Pedro LD, et al. Neuropilin‐1 facil-
itates SARS‐CoV‐2 cell entry and infectivity. Science. 2020;370:
856‐860.
78. Helal MA, Shouman S, Abdelwaly A, et al. Molecular basis of the
potential interaction of SARS‐CoV‐2 spike protein to CD147 in
COVID‐19 associated‐lymphopenia. J Biomol Struct Dyn. 2020:1‐11.
https://doi.org/10.1080/07391102.2020.1822208
79. Latini A, Agolini E, Novelli A, et al. COVID‐19 and genetic variants
of protein involved in the SARS‐CoV‐2 entry into the host cells.
Genes. 2020;11(9).
80. Strollo R, Pozzilli P. DPP4 inhibition: preventing SARS‐CoV‐2 in-
fection and/or progression of COVID‐19? Diabetes Metab Res Rev.
2020;36:e3330.
81. Raha AA, Chakraborty S, Henderson J, et al. Investigation of CD26, a
potential SARS‐CoV‐2 receptor, as a biomarker of age and pathology.
Biosci Rep. 2020;40(12). https://doi.org/10.1042/BSR20203092
82. Kotani N, Nakano T. Candidate screening of host cell membrane
proteins involved in SARS‐CoV‐2 entry. bioRxiv. 2020. https://doi.
org/10.1101/2020.09.09.289488
83. Amraei R, Napoleon M, Yin W, et al. CD209L/L‐SIGN and CD209/
DC‐SIGN act as receptors for SARS‐CoV‐2 and are differentially
expressed in lung and kidney epithelial and endothelial cells.
bioRxiv. 2020. https://doi.org/10.1101/2020.06.22.165803
84. Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H.
Tissue distribution of ACE2 protein, the functional receptor for
SARS coronavirus. A first step in understanding SARS pathogen-
esis. J Pathol. 2004;203:631‐637.
85. Deigendesch N, Sironi L, Kutza M, et al. Correlates of critical illness‐
related encephalopathy predominate postmortem COVID‐19
neuropathology. Acta Neuropathol. 2020;140:583‐586.
86. Al‐Dalahmah O, Thakur KT, Nordvig AS, et al. Neuronophagia and
microglial nodules in a SARS‐CoV‐2 patient with cerebellar he-
morrhage. Acta Neuropathol Commun. 2020;8:147.
87. Kantonen J, Mahzabin S, Mäyränpää MI, et al. Neuropathologic
features of four autopsied COVID‐19 patients. Brain Pathol. 2020.
https://doi.org/10.1111/bpa.12889
88. Jensen MP, Le Quesne J, Officer‐Jones L, et al. Neuropathological
findings in two patients with fatal COVID‐19. Neuropathol Appl
Neurobiol. 2020;nan12662. https://doi.org/10.1111/nan.12662
89. He L, Mäe MA, Sun Y, et al. Pericyte‐specific vascular expression of
SARS‐CoV‐2 receptor ACE2‐ implications for microvascular in-
flammation and hypercoagulopathy in COVID‐19 patients. bioRxiv.
2020. https://doi.org/10.1101/2020.05.11.088500
90. Chen R, Wang K, Yu J, et al. The spatial and cell‐type distribution of
SARS‐CoV‐2 receptor ACE2 in human and mouse brain. bioRxiv. 2020.
https://doi.org/10.1101/2020.04.07.030650
91. Deffner F, Scharr M, Klingenstein S, et al. Histological evidence for
the enteric nervous system and the choroid plexus as alternative
routes of neuroinvasion by SARS‐CoV2. Front Neuroanat. 2020;14:
596439.
92. Nampoothiri S, Sauve F, Ternier G, et al. The hypothalamus as a hub
for SARS‐CoV‐2 brain infection and pathogenesis. bioRxiv. 2020.
https://doi.org/10.1101/2020.06.08.139329
93. Murta V, Villarreal A, Ramos AJ. Severe acute respiratory syn-
drome coronavirus 2 impact on the central nervous system: are
astrocytes and microglia main players or merely bystanders? ASN
Neuro. 2020;12:1759091420954960.
94. Brann DH, Tsukahara T, Weinreb C, et al. Non‐neuronal expression
of SARS‐CoV‐2 entry genes in the olfactory system suggests me-
chanisms underlying COVID‐19‐associated anosmia. Sci Adv. 2020;
6(31):eabc5801.
| 1997
95. Chiappelli F. Towards neuro‐COVID‐19. Bioinformation. 2020;16:
288‐292.
96. Merad M, Martin JC. Pathological inflammation in patients with
COVID‐19: a key role for monocytes and macrophages. Nat Rev
Immunol. 2020;20:355‐362.
97. Martines RB, Ritter JM, Matkovic E, et al. Pathology and patho-
genesis of SARS‐CoV‐2 associated with fatal coronavirus disease,
United States. Emerg Infect Dis. 2020;26:2005‐2015.
98. Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS‐CoV‐2 receptor
ACE2 is an interferon‐stimulated gene in human airway epithelial
cells and is detected in specific cell subsets across tissues. Cell.
2020;181:1016‐1035.
99. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and
endotheliitis in COVID‐19. Lancet. 2020;395:1417‐1418.
100. Avula A, Nalleballe K, Narula N, et al. COVID‐19 presenting as
stroke. Brain Behav Immun. 2020;87:115‐119.
101. Cardot‐Leccia N, Hubiche T, Dellamonica J, Burel‐Vandenbos F,
Passeron T. Pericyte alteration sheds light on micro‐vasculopathy
in COVID‐19 infection. Intensive Care Med. 2020;46:1777‐1778.
102. Domingues RB, Mendes‐Correa MC, de Moura Leite FBV, et al. First
case of SARS‐COV‐2 sequencing in cerebrospinal fluid of a patient
with suspected demyelinating disease. J Neurol. 2020;267:2‐4.
103. Huang YH, Jiang D, Huang JT. SARS‐CoV‐2 detected in cere-
brospinal fluid by PCR in a case of COVID‐19 encephalitis. Brain
Behav Immun. 2020;87:149.
104. Muffat J, Li Y, Omer A, et al. Human induced pluripotent stem cell‐
derived glial cells and neural progenitors display divergent re-
sponses to Zika and dengue infections. Proc Natl Acad Sci U S A.
2018;115:7117‐7122.
105. Butowt R, Bilinska K. SARS‐CoV‐2: Olfaction, brain infection, and
the urgent need for clinical samples allowing earlier virus detec-
tion. ACS Chem Neurosci. 2020;11:1200‐1203.
106. Politi LS, Salsano E, Grimaldi M. Magnetic resonance imaging al-
teration of the brain in a patient with coronavirus disease 2019
(COVID‐19) and anosmia. JAMA Neurology. 2020;77:1028‐1029.
107. Kaye R, Chang CWD, Kazahaya K, Brereton J, Denneny JC.
COVID‐19 anosmia reporting tool: initial findings. Otolaryngol Head
Neck Surg. 2020;163:132‐134.
108. Lechien JR, Chiesa‐Estomba CM, De Siati DR, et al. Olfactory and
gustatory dysfunctions as a clinical presentation of mild‐to‐moderate
forms of the coronavirus disease (COVID‐19): a multicenter European
study. Eur Arch Otrhinolaryngol. 2020;277:2251‐2261.
109. Bilinska K, Jakubowska P, Von Bartheld CS, Butowt R. Expression
of the SARS‐CoV‐2 entry proteins, ACE2 and TMPRSS2, in cells of
the olfactory epithelium: identification of cell types and trends
with age. ACS Chem Neurosci. 2020;11:1555‐1562.
110. Parma V, Ohla K, Veldhuizen MG, et al. More than smell‐COVID‐19
is associated with severe impairment of smell, taste, and che-
mesthesis. Chem Senses. 2020;45:609‐622.
111. Torabi A, Mohammadbagheri E, Akbari Dilmaghani N, et al. Proin-
flammatory cytokines in the olfactory mucosa result in COVID‐19
induced anosmia. ACS Chem Neurosci. 2020;11:1909‐1913.
112. Samaranayake LP, Fakhruddin KS, Panduwawala C. Sudden onset,
acute loss of taste and smell in coronavirus disease 2019 (COVID‐19):
a systematic review. Acta Odontol Scand. 2020;78:467‐473.
113. Biadsee A, Biadsee A, Kassem F, Dagan O, Masarwa S, Ormianer Z.
Olfactory and oral manifestations of COVID‐19: sex‐related
symptoms—a potential pathway to early diagnosis. Otolaryngol
Head Neck Surg. 2020;163:722‐728.
114. Shiers S, Ray PR, Wangzhou A, et al. ACE2 and SCARF expression
in human dorsal root ganglion nociceptors: implications for
SARS‐CoV‐2 virus neurological effects. Pain. 2020;161:2494‐2501.
115. Hirose R, Ikegaya H, Naito Y, et al. Survival of SARS‐CoV‐2 and
influenza virus on the human skin: importance of hand hygiene in
1998 | BODNAR
COVID‐19. Clin Infect Dis. 2020. ciaa1517. https://doi.org/10.
1093/cid/ciaa1517
116. Agarwal A, Chen A, Ravindran N, To C, Thuluvath PJ. Gastro-
intestinal and liver manifestations of COVID‐19. J Clin Exp Hepatol.
2020;10:263‐265.
117. Cheung KS, Hung IFN, Chan PPY, et al. Gastrointestinal manifes-
tations of SARS‐CoV‐2 Infection and virus load in fecal samples
from a Hong Kong cohort: systematic review and meta‐analysis.
Gastroenterology. 2020;159:81‐95.
118. Shahbazi R, Yasavoli‐Sharahi H, Alsadi N, Ismail N, Matar C. Pro-
biotics in treatment of viral respiratory infections and neuroin-
flammatory disorders. Molecules. 2020;25:4891.
119. Ferguson AV Circumventricular organs: integrators of circulating
signals controlling hydration, energy balance, and immune func-
tion. In: De Luca LA, Jr, Menani JV, Johnson AK, editors. Neuro-
biology of Body Fluid Homeostasis: Transduction and Integration. Boca
Raton, FL: CRC Press/Taylor & Francis; 2014.
120. Kim J, Alejandro B, Hetman M, et al. Zika virus infects pericytes in
the choroid plexus and enters the central nervous system through
the blood‐cerebrospinal fluid barrier. PLOS Pathog. 2020;16:
e1008204.
121. Alam SB, Willows S, Kulka M, Sandhu JK. Severe acute re-
spiratory syndrome coronavirus 2 may be an underappreciated
ET AL.
pathogen of the central nervous system. Eur J Neurol. 2020;27:
2348‐2360.
122. Kramer‐Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack‐
Werner R. Cells of the central nervous system as targets and re-
servoirs of the human immunodeficiency virus. Virus Res. 2005;
111:194‐213.
123. Codo AC, Davanzo GG, Monteiro LB, et al. Elevated glucose levels
favor SARS‐CoV‐2 infection and monocyte response through a
HIF‐1alpha/glycolysis‐dependent axis. Cell Metab. 2020;32:
437‐446.
124. Oprinca GC, Muja LA. Postmortem examination of three
SARS‐CoV‐2‐positive autopsies including histopathologic and im-
munohistochemical analysis. Int J Legal Med. 2020. https://doi.org/
10.1007/s00414-020-02406-w
How to cite this article: Bodnar B, Patel K, Ho W, Luo JJ, Hu
W. Cellular mechanisms underlying neurological/
neuropsychiatric manifestations of COVID‐19. J Med Virol.
2021;93:1983–1998. https://doi.org/10.1002/jmv.26720