The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients

Abstract

Following the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), another highly pathogenic coronavirus named SARS-CoV-2 (previously known as 2019-nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS-CoV, and causes acute, highly lethal pneumonia (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV. The most characteristic symptom of COVID-19 patients is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some COVID-19 patients also showed neurologic signs such as headache, nausea and vomiting. Increasing evidence shows that coronavriruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS-CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechano- and chemoreceptors in the lung and lower respiratory airways. In light of the high similarity between SARS-CoV and SARS-CoV2, it is quite likely that the potential invasion of SARS-CoV2 is partially responsible for the acute respiratory failure of COVID-19 patients. Awareness of this will have important guiding significance for the prevention and treatment of the SARS-CoV-2-induced respiratory failure. (229 words) This article is protected by copyright. All rights reserved.

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J Med Virol. 2020;1–4. wileyonlinelibrary.com/journal/jmv © 2020 Wiley Periodicals, Inc.
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1
Received: 14 February 2020
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Accepted: 24 February 2020
DOI: 10.1002/jmv.25728
REVIEW
The neuroinvasive potential of SARS‐CoV2 may play a role
in the respiratory failure of COVID‐19 patients
Yan‐Chao Li
1
|Wan‐Zhu Bai
2
|Tsutomu Hashikawa
3
1
Department of Histology and Embryology,
College of Basic Medical Sciences, Norman
Bethune College of Medicine, Jilin University,
Changchun, Jilin, China
2
Institute of Acupuncture and Moxibustion,
China Academy of Chinese Medical Science,
Beijing, China
3
Neural Architecture, Advanced Technology
Development Group, RIKEN Brain Science
Institute, Saitama, Japan
Correspondence
Yan‐Chao Li, Department of Histology and
Embryology, College of Basic Medical Sciences,
Norman Bethune College of Medicine, Jilin
University, Changchun, 130021 Jilin, China.
Email: liyanchao@jlu.edu.cn
Abstract
Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and
Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly patho-
genic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in
December 2019 in Wuhan, China, and rapidly spreads around the world. This virus
shares highly homological sequence with SARS‐CoV, and causes acute, highly lethal
pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to
those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of
patients with COVID‐19 is respiratory distress, and most of the patients admitted to
the intensive care could not breathe spontaneously. Additionally, some patients with
COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting.
Increasing evidence shows that coronaviruses are not always confined to the re-
spiratory tract and that they may also invade the central nervous system inducing
neurological diseases. The infection of SARS‐CoV has been reported in the brains
from both patients and experimental animals, where the brainstem was heavily
infected. Furthermore, some coronaviruses have been demonstrated able to spread via a
synapse‐connected route to the medullary cardiorespiratory center from the mechan-
oreceptors and chemoreceptors in the lung and lower respiratory airways. Considering
the high similarity between SARS‐CoV and SARS‐CoV2, it remains to make clear whether
the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory
failure of patients with COVID‐19. Awareness of this may have a guiding significance for
the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.
KEYWORDS
cell susceptibility, coronavirus, dissemination, nervous system
1|INTRODUCTION
Coronaviruses (CoVs), which are large enveloped non‐segmented
positive‐sense RNA viruses, generally cause enteric and re-
spiratory diseases in animals and humans.
1
Most human CoVs,
such as hCoV‐229E, OC43, NL63, and HKU1 cause mild re-
spiratory diseases, but the worldwide spread of two previously
unrecognized CoVs, the severe acute respiratory syndrome
CoV (SARS‐CoV) and Middle East respiratory syndrome CoV
(MERS‐Co V) ha ve called global attention to the lethal potential of
human CoVs.
2
While MERS‐CoV is still not eliminated from the world,
another highly pathogenic CoV, currently named SARS‐CoV‐2 (previously
known as 2019‐nCoV), emerged in December 2019 in Wuhan, China.
This novel CoV has caused a national outbreak of severe pneumonia
(coronavirus disease 2019 [COVID‐19]) in China, and rapidly spreads
around the world.
[Correction added on March 17, 2020 after first online publication: Manuscript has been revised with author's latest changes]

Genomic analysis shows that SARS‐CoV‐2 is in the same beta-
coronavirus (βCoV) clade as MERS‐CoV and SARS‐CoV, and shares
highly homological sequence with SARS‐CoV.
3
The public evidence
shows that COVID‐19 shares similar pathogenesis with the pneu-
monia induced by SARS‐CoV or MERS‐CoV.
4
Moreover, the entry of
SARS‐CoV‐2 into human host cells has been identified to use the
same receptor as SARS‐CoV.
5,6
Most CoVs share a similar viral structure and infection
pathway,
7,8
and therefore the infection mechanisms previously
found for other CoVs may also be applicable for SARS‐CoV‐2.
A growing body of evidence shows that neurotropism is one
common feature of CoVs.
1,9‐12
Therefore, it is urgent to make
clear whether SARS‐CoV‐2 can gain access to the central nervous
system (CNS) and induce neuronal injury leading to the acute
respiratory distress.
2|THE CLINICAL FEATURES OF
SARS‐CoV‐2INFECTION
SARS‐CoV‐2 causes acute, highly lethal pneumonia with clinical
symptoms similar to those reported for SARS‐CoV and MERS‐CoV.
2,11
Imaging examination revealed that most patients with fever, dry
cough, and dyspnea showed bilateral ground‐glass opacities on chest
computerized tomography scans.
12
However, different from SARS‐
CoV, SARS‐CoV‐2‐infected patients rarely showed prominent upper
respiratory tract signs and symptoms, indicating that the target cells of
SARS‐CoV‐2 may be located in the lower airway.
2
Based upon the first‐hand evidence from Wuhan local
hospitals,
2,10,12
the common symptoms of COVID‐19 were fever
(83%‐99%) and dry cough (59.4%‐82%) at the onset of illness.
However, the most characteristic symptom of patients is re-
spiratory distress (~55%). Among the patients with dyspnea,
more than half needed intensive care. About 46% to 65% of the
patients in the intensive care worsened in a short period of time
and died due to respiratory failure. Among the 36 cases in the
intensive care reported by Wang et al,
10
11.1% received high‐
flow oxygen therapy, 41.7% received noninvasive ventilation, and
47.2% received invasive ventilation. These data suggest that most
(about 89%) of the patients in need of intensive care could not
breathe spontaneously.
It is now known that CoVs are not always confined to the
respiratory tract and that they may also invade the CNS inducing
neurological diseases. Such neuroinvasive propensity of CoVs has
been documented almost for all the βCoVs, including SARS‐CoV,
1
MERS‐CoV,
13
HCoV‐229E,
14
HCoV‐OC43,
15
mouse hepatitis
virus,
16
and porcine hemagglutinating encephalomyelitis
coronavirus (HEV).
9,17‐19
With respect to the high similarity between SARS‐CoV and
SARS‐CoV2, it remains to know whether the potential neuroinvasion
of SARS‐CoV‐2 plays a role in the acute respiratory failure of patients
with COVID‐19.
3|THE NEUROINVASIVE POTENTIAL OF
SARS‐CoV‐2
It is believed that the tissue distributions of host receptors are
generally consistent with the tropisms of viruses.
20‐22
The entry of
SARS‐CoV into human host cells is mediated mainly by a cellular
receptor angiotensin‐converting enzyme 2 (ACE2), which is ex-
pressed in human airway epithelia, lung parenchyma, vascular en-
dothelia, kidney cells, and small intestine cells.
23‐25
Different from
SARS‐CoV, MERS‐CoV enters human host cells mainly via dipeptidyl
peptidase 4 (DPP4), which is present in the lower respiratory tract,
kidney, small intestine, liver, and the cells of the immune system.
26,27
However, the presence of ACE2 or DPP4 solely is not sufficient
to make host cells susceptible to infection. For example, some ACE2‐
expressing endothelial cells and human intestinal cell lines failed to
be infected by SARS‐CoV,
28,29
while some cells without a detectable
expression level of ACE2, such as hepatocytes could also be infected
by SARS‐CoV.
20
Likewise, the infection of SARS‐CoV or MERS‐CoV
was also reported in the CNS, where the expression level of ACE2
30
or DDP4
30
is very low under normal conditions.
Early in 2002 and 2003, studies on the samples from patients
with SARS have demonstrated the presence of SARS‐CoV particles
in the brain, where they were located almost exclusively in the
neurons.
31‐33
Experimental studies using transgenic mice further
revealed that either SARS‐CoV
34
or MERS‐COV,
13
when given in-
tranasally, could enter the brain, possibly via the olfactory nerves,
and thereafter rapidly spread to some specific brain areas including
thalamus and brainstem. It is noteworthy that in the mice infected
with low inoculum doses of MERS‐CoV virus particles were de-
tected only in the brain, but not in the lung, which indicates that the
infection in the CNS was more important for the high mortality
observed in the infected mice.
13
Among the involved brain areas,
the brainstem has been demonstrated to be heavily infected by
SARS‐CoV
34,35
or MERS‐CoV.
13
The exact route by which SARS‐CoV or MERS‐COV enters the
CNS is still not reported. However, hematogenous or lymphatic route
seems impossible, especially in the early stage of infection, since al-
most no virus particle was detected in the nonneuronal cells in the
infected brain areas.
31‐33
On the other hand, increasing evidence
shows that CoVs may first invade peripheral nerve terminals, and
then gain access to the CNS via a synapse‐connected route.
9,17,19,36
The trans‐synaptic transfer has been well documented for other
CoVs, such as HEV67
9‐10,18‐19
and avian bronchitis virus.
36,37
HEV 67N is the first CoV found to invade the porcine brain, and
it shares more than 91% homology with HCoV‐OC43.
38,39
HEV first
oronasally infects the nasal mucosa, tonsil, lung, and small intestine in
suckling piglets, and then is delivered retrogradely via peripheral
nerves to the medullary neurons in charge of peristaltic function of
the digestive tract, resulting in the so‐called vomiting diseases.
18,19
The transfer of HEV 67N between neurons has been demonstrated
by our previous ultrastructural studies to use the clathrin‐coating‐
mediated endocytotic/exocytotic pathway.
17
2
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LI ET AL.

Similarly, the trans‐synaptic transfer has been reported for avian
bronchitis virus.
36,37
Intranasal inoculation in mice with avian influ-
enza virus was reported to cause neural infection besides bronchitis
or pneumonia.
36
Of interest, viral antigens have been detected in the
brainstem, where the infected regions included the nucleus of the
solitary tract and nucleus ambiguus. The nucleus of the solitary tract
receives sensory information from the mechanoreceptors and che-
moreceptors in the lung and respiratory tracts,
40‐42
while the effer-
ent fibers from the nucleus ambiguus and the nucleus of the solitary
tract provide innervation to airway smooth muscle, glands, and blood
vessels. Such neuroanatomic interconnections indicate that the death
of infected animals or patients may be due to the dysfunction of the
cardiorespiratory center in the brainstem.
11,30,36
Taken together, the neuroinvasive propensity has been demon-
strated as a common feature of CoVs. In light of the high similarity
between SARS‐CoV and SARS‐CoV2, it is quite likely that SARS‐
CoV‐2 also possesses a similar potential. Based on an epidemiological
survey on COVID‐19, the median time from the first symptom to
dyspnea was 5.0 days, to hospital admission was 7.0 days, and to the
intensive care was 8.0 days.
10
Therefore, the latency period may be
enough for the virus to enter and destroy the medullary neurons. As
a matter of fact, the previous studies
2,14‐15
mentioned above has re-
ported that some patients infected with SARS‐CoV‐2 did show neurologic
signs such as headache (about 8%), nausea and vomiting (1%). More
recently, one study on 214 COVID‐19 patients by Mao et al.
43
further
found that about 88% (78/88) among the severe patients displayed
neurologic manifestations including acute cerebrovascular diseases and
impaired consciousness. Therefore, awareness of the possible neu-
roinvasion may have a guiding significance for the prevention and
treatment of the SARS‐CoV‐2‐induced respiratory failure.
ORCID
Yan‐Chao Li http://orcid.org/0000-0002-2884-9829
REFERENCES
1. Glass WG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host
defense following severe acute respiratory syndrome‐coronavirus (SARS‐
CoV) pulmonary infection of mice. J Immunol. 2004;173:4030‐4039.
2. 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.
3. Yu F, Du L, Ojcius DM, Pan C, Jiang S. Measures for diagnosing and
treating infections by a novel coronavirus responsible for a pneu-
monia outbreak originating in Wuhan, China. Microbes Infect. 2020.
https://doi.org/10.1016/j.micinf.2020.01.003
4. Song Z, Xu Y, Bao L, et al. From SARS to MERS, thrusting cor-
onaviruses into the spotlight. Viruses. 2019;11:59. https://doi.org/10.
3390/v11010059
5. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of
2019 novel coronavirus: implications for virus origins and receptor
binding. Lancet. 2020;395:565‐574.
6. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by
novel coronavirus from Wuhan: an analysis based on decade‐long
structural studies of SARS. J Virol. 2020. https://doi.org/10.1128/JVI.
00127‐20
7. Yuan Y, Cao D, Zhang Y, et al. Cryo‐EM structures of MERS‐CoV and
SARS‐CoV spike glycoproteins reveal the dynamic receptor binding
domains. Nat Commun. 2017;8:15092.
8. Hulswit RJ, de Haan CA, Bosch BJ. Coronavirus spike protein and
tropism changes. Adv Virus Res. 2016;96:29‐57.
9. Li YC, Bai WZ, Hirano N, Hayashida T, Hashikawa T. Coronavirus
infection of rat dorsal root ganglia: ultrastructural characterization of
viral replication, transfer, and the early response of satellite cells.
Virus Res. 2012;163:628‐635.
10. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized
patients with 2019 novel coronavirus‐infected pneumonia in Wuhan,
China. JAMA. 2020. https://doi.org/10.1001/jama.2020.1585
11. Khan S, Ali A, Siddique R, Nabi G. Novel coronavirus is putting the
whole world on alert. J Hosp Infect. 2020. https://doi.org/10.1016/j.
jhin.2020.01.019
12. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical
characteristics of 99 cases of 2019 novel coronavirus pneumonia
in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):
507‐513.
13. Li K, Wohlford‐Lenane C, Perlman S, et al. Middle East respiratory
syndrome coronavirus causes multiple organ damage and lethal dis-
ease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis.
2016;213:712‐722.
14. Talbot PJ, Ekandé S, Cashman NR, Mounir S, Stewart JN. Neurotropism
of human coronavirus 229E. Adv Exp Med Biol. 1993;342:339‐346.
15. Dubé M, Le Coupanec A, Wong AHM, Rini JM, Desforges M,
Talbot PJ. Axonal transport enables neuron‐to‐neuron propagation of
human coronavirus OC43. J Virol. 2018;92, https://doi.org/10.1128/
JVI.00404‐18
16. Zhou X, Huang F, Xu L, et al. Hepatitis E virus infects neurons and
brains. J Infect Dis. 2017;215(8):1197‐1206.
17. Li YC, Bai WZ, Hirano N, et al. Neurotropic virus tracing suggests a
membranous‐coating‐mediated mechanism for transsynaptic com-
munication. J Comp Neurol. 2013;521:203‐212.
18. Mengeling WL, Boothe AD, Ritchie AE. Characteristics of a cor-
onavirus (strain 67N) of pigs. Am J Vet Res. 1972;33(2):297‐308.
19. Andries K, Pensaert MB. Immunofluorescence studies on the patho-
genesis of hemagglutinating encephalomyelitis virus infection in pigs
after oronasal inoculation. Am J Vet Res. 1980;41(9):1372‐1378.
20. To KF, Lo AW. Exploring the pathogenesis of severe acute respiratory
syndrome (SARS): the tissue distribution of the coronavirus (SARS‐
CoV) and its putative receptor, angiotensin‐converting enzyme 2
(ACE2). J Pathol. 2004;203:740‐743.
21. Tang JW, To KF, Lo AW, Sung JJ, Ng HK, Chan PK. Quantitative
temporal‐spatial distribution of severe acute respiratory syndrome‐
associated coronavirus (SARS‐CoV) in post‐mortem tissues. J Med
Virol. 2007;79:1245‐1253.
22. Kam YW, Okumura Y, Kido H, Ng LF, Bruzzone R, Altmeyer R.
Cleavage of the SARS coronavirus spike glycoprotein by airway pro-
teases enhances virus entry into human bronchial epithelial cells in
vitro. PLoS One. 2009;4(11):e7870.
23. Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin‐
converting enzyme‐related carboxypeptidase (ACE2) converts an-
giotensin I to angiotensin 1‐9. Circ Res. 2000;87(5):E1‐E9.
24. Harmer D, Gilbert M, Borman R, Clark KL. Quantitative mRNA ex-
pression profiling of ACE 2, a novel homologue of angiotensin con-
verting enzyme. FEBS Lett. 2002;532:107‐110.
25. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H.
Tissue distribution of ACE2 protein, the functional receptor for SARS
coronavirus. A first step in understanding SARS pathogenesis. JPathol.
2004;203(2):631‐637.
26. Mattern T, Scholz W, Feller AC, Flad HD, Ulmer AJ. Expression of
CD26 (dipeptidyl peptidase IV) on resting and activated human
T‐lymphocytes. Scand J Immunol. 1991;33:737‐748.
27. Boonacker E, Van Noorden CJ. The multifunctional or moonlighting
protein CD26/DPPIV. Eur J Cell Biol. 2003;82:53‐73.
28. Chan PK, To KF, Lo AW, et al. Persistent infection of SARS cor-
onavirus in colonic cells in vitro. J Med Virol. 2004;74:1‐7.
LI ET AL.
|
3

29. Ding Y, Wang H, Shen H, et al. The clinical pathology of severe acute
respiratory syndrome (SARS): a report from China. J Pathol. 2003;200:
282‐289.
30. Bernstein HG, Dobrowolny H, Keilhoff G, Steiner J. Dipeptidyl
peptidase IV, which probably plays important roles in alzheimer
disease (AD) pathology, is upregulated in AD brain neurons
and associates with amyloid plaques. Neurochem Int. 2018;114:
55‐57.
31. Ding Y, He L, Zhang Q, et al. Organ distribution of severe acute re-
spiratory syndrome (SARS) associated coronavirus (SARS‐CoV) in
SARS patients: implications for pathogenesis and virus transmission
pathways. J Pathol. 2004;203:622‐630.
32. Gu J, Gong E, Zhang B, et al. Multiple organ infection and the pa-
thogenesis of SARS. J Exp Med. 2005;202(3):415‐424.
33. Xu J, Zhong S, Liu J, et al. Detection of severe acute respiratory
syndrome coronavirus in the brain: potential role of the chemokine
mig in pathogenesis. Clin Infect Dis. 2005;41:1089‐1096.
34. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe
acute respiratory syndrome coronavirus infection causes neuronal
death in the absence of encephalitis in mice transgenic for human
ACE2. J Virol. 2008;82:7264‐7275.
35. McCray PB Jr, Pewe L, Wohlford‐Lenane C, et al. Lethal infection of
K18‐hACE2 mice infected with severe acute respiratory syndrome
coronavirus. J Virol. 2007;81:813‐821.
36. Matsuda K, Park CH, Sunden Y, et al. The vagus nerve is one route of
transneural invasion for intranasally inoculated influenza a virus in
mice. Vet Pathol. 2004;41:101‐107.
37. Chasey D, Alexander DJ. Morphogenesis of avian infectious bronchitis
virus in primary chick kidney cells. Arch Virol. 1976;52:101‐111.
38. González JM, Gomez‐Puertas P, Cavanagh D, Gorbalenya AE, Enjuanes L.
A comparative sequence analysis to revise the current taxonomy of the
family coronaviridae. Arch Virol. 2003;148:2207‐2235.
39. Li Z, He W, Lan Y, et al. The evidence of porcine hemagglutinating
encephalomyelitis virus induced nonsuppurative encephalitis as the
cause of death in piglets. Peer J. 2016;4:e2443.
40. Kalia M, Mesulam MM. Brain stem projections of sensory and motor
components of the vagus complex in the cat: II. Laryngeal, tracheo-
bronchial, pulmonary, cardiac, and gastrointestinal branches. J Comp
Neurol. 1980;193:467‐508.
41. Hadziefendic S, Haxhiu MA. CNS innervation of vagal preganglionic
neurons controlling peripheral airways: a transneuronal labeling study
using pseudorabies virus. J Auton Nerv Syst. 1999;76:135‐145.
42. Raux H, Flamand A, Blondel D. Interaction of the rabies virus P pro-
tein with the LC8 dynein light chain. J Virol. 2000;74:10212‐10216.
43. Mao L, Wang M, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D,
Li Y, Jin H, Hu B. Neurological Manifestations of Hospitalized Patients
with COVID-19 in Wuhan, China: a retrospective case series study.
MedRxiv.https://doi.org/10.1101/2020.02.22.20026500
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How to cite this article: Li Y‐C, Bai W‐Z, Hashikawa T. The
neuroinvasive potential of SARS‐CoV2 may play a role in the
respiratory failure of COVID‐19 patients. J Med Virol.
2020;1–4. https://doi.org/10.1002/jmv.25728
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LI ET AL.