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The brain, another potential target organ, needs early protection from SARS-CoV-2 neuroinvasion

March 2020
Science China. Life sciences 63(5)

March 2020
63(5)

DOI:10.1007/s11427-020-1690-y

Authors:

Zhengqian Li

Peking University Third Hospital

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•INSIGHT•https://doi.org/10.1007/s11427-020-1690-y

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The brain, another potential target organ, needs early protection

from SARS-CoV-2 neuroinvasion

Zhengqian Li1, Yuguang Huang2& Xiangyang Guo1*

1Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China;

2Department of Anesthesiology, Peking Union Medical College Hospital, Beijing 100730, China

Received March 12, 2020; accepted March 29, 2020; published online March 31, 2020

Citation: Li, Z., Huang, Y., and Guo, X. (2020). The brain, another potential target organ, needs early protection from SARS-CoV-2 neuroinvasion. Sci China

Life Sci 63, https://doi.org/10.1007/s11427-020-1690-y

With the outbreak of the novel coronavirus disease (COVID-

19) in China and rapid spread in other countries around the

world, humans are engaged in a life-and-death battle with the

severe acute respiratory syndrome coronavirus 2 (SARS-

CoV-2), formerly known as 2019-Novel Coronavirus (2019-

nCoV). Based on the existing evidence and lessons from

SARS outbreak in 2003, our attention should not be confined

to the general organs whose dysfunctions were relatively

easy to be observed or examined such as lung, kidney, and

liver; at the same time, the brain should not be neglected due

to the potential neuroinvasion of SARS-CoV-2, which

prompts us to keep an alert on the onset of neurological

symptoms, early diagnostics, and neuroprotection.

On March 3, the National Health Commission of China

issued an updated version of the diagnosis and treatment

guidelines for COVID-19 (China NHCotPsRo, 2020). In the

latest version of the guidelines, the pathological description

was based on a small number of human histopathological

samples. These showed that multiple organs are involved,

including lungs, spleen and hilar lymph nodes, heart and

blood vessels, liver and gallbladder, kidney, brain, adrenal

gland, esophagus, stomach, and intestines. Specifically,

edema and partial neuronal degeneration were observed in

brain tissues (China NHCotPsRo, 2020). A proportion of

COVID-19 patients in Wuhan city presented with neurologic

signs such as headache (about 8%), nausea and vomiting

(1%) (Chen et al., 2020). A retrospective case series of 214

COVID-19 patients reported that up to 36.4% of patients had

neurologic symptoms manifested as acute cerebrovascular

diseases, consciousness impairment and skeletal muscle

symptoms (Mao et al., 2020). Furthermore, a COVID-19

patient was diagnosed with viral encephalitis in Beijing Di-

tan Hospital by Jingyuan Liu. The presence of SARS-CoV-2

in cerebrospinal fluid was confirmed later by gene sequen-

cing (unpublished data). As shown in Figure 1, these findings

suggest that COVID-19 patients should be treated promptly

to reduce complications beyond the lungs. This may decrease

the mortality rate.

As a member of the family of coronaviruses (CoVs), the

pathogen SARS-CoV-2 shares a highly homologous se-

quence with the SARS-CoV and Middle East respiratory

syndrome CoV (MERS-CoV). Previous studies have shown

that the brain was a major target organ for infections from

almost all the betacoronaviruses, including SARS-CoV and

MERS-CoV, both in patients and experimental animals (Li et

al., 2020). In light of the structural similarity between SARS-

CoV2 and betacoronaviruses, it is highly suspected that

SARS-CoV-2 also possesses similar neuroinvasive and

neurotrophic properties. In addition, SARS-CoV-2 and

SARS-CoV shared the same host receptor with the human

angiotensin-converting enzyme 2 (ACE2) (Hamming et al.,

2004), an important component of the brain renin-angio-

tensin system (RAS). The existence of an independent in-

trinsic cerebral RAS with all its components has been well

established. So far, no direct evidence of entry of SARS-

SCIENCE CHINA

Life Sciences

*Corresponding author (email: puthmzk@hsc.pku.edu.cn)

Downloaded to IP: 10.159.164.174 On: 2020-03-31 05:43:53 http://engine.scichina.com/doi/10.1007/s11427-020-1690-y

CoV-2 into the CNS has been reported in any international

peer-reviewed journal, although some researchers have

proposed that the neuroinvasive potential of SARS-CoV2

may be at least partially responsible for the respiratory fail-

ure of COVID-19 patients (Li et al., 2020). Actually, human

respiratory viruses may enter the CNS through different

routes involving the vasculature, the olfactory and trigeminal

nerves, the cerebrospinal fluid, and the lymphatic system

(Desforges et al., 2020). We suggest that the infection me-

chanisms previously found for SARS-CoV may be applic-

able for SARS-CoV-2 and we have to be vigilant about the

neuroinvasion of SARS-CoV-2 in the CNS until solid pa-

thological evidence is available.

It should be emphasized that COVID-19 patients will be

facing both neuropsychological and neurological challenges.

On the one hand, with the rapid transmission of life-threa-

tening pneumonia, self-quarantine and medical observations

not only increase the possibility of psychological and mental

problems, including anxiety and depression, but also reduce

the availability of timely psychological intervention. Even

one year after the outbreak, SARS survivors still had ele-

vated stress levels and worrying levels of psychological

distress (Lee et al., 2007). On the other hand, viral dis-

semination in brain tissue may be accompanied by neu-

roinflammation and vascular endothelium dysfunction,

which have been reported to contribute to cognitive im-

pairment, especially in frail or elderly patients (Toth et al.,

2017). These changes may be much worse under the hypoxic

conditions of acute respiratory distress syndrome caused by

SARS-CoV-2.

Awareness of the potential neuroinvasion of SARS-CoV-2

will have critical significance for the prevention and treat-

ment of COVID-19. Early antiviral therapy with neuropro-

tective effects should be taken as soon as possible. For

example, clear lung detoxification soup, a classical pre-

scription of traditional Chinese medicine combination, has

been shown to be an effective treatment based on syndrome

differentiation (China NHCotPsRo, 2020). In addition,

clinical physical examination including the pupillary light

reflex and a variety of tendon reflexes, and pathogenic de-

tection of cerebrospinal fluid should be considered, if clini-

cally available, for timely identification and management of

neurological complications. Furthermore, prompt en-

dotracheal intubation and mechanical respiratory support at

the earliest sign of ineffective noninvasive ventilation should

be proposed, since the central respiratory failure progresses

rapidly after the SARS-CoV-2’s entry into the CNS and

damages the brainstem where the pneumotaxic center is lo-

cated (Li et al., 2020). It is also worth mentioning that the

long-term psychological and neurocognitive implications of

COVID-19 should not be ignored. Last but not the least, the

effective vaccine with safety profile and antiviral drugs that

can cross the blood-brain barrier are urgently needed.

Compliance and ethics The author(s) declare that they have no conflict

of interests.

Acknowledgements This work was supported by Peking University

“Clinical Medicine plus X” Youth Project (PKU2020LCXQ016) and the

National Natural Science Foundation of China (81971012, 81873726).

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Figure 1 (Color online) A timeline of events for the notice of neurological manifestations in COVID-19 patients.

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Article

Oct 2016

Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. Understanding and targeting the age-related pathophysiological mechanisms that underlie vascular contributions to cognitive impairment and dementia (VCID) is expected to have a major role in preserving brain health in older individuals. Maintenance of cerebral perfusion, protecting the microcirculation from high pressure-induced damage and moment-to-moment adjustment of regional oxygen and nutrient supply to changes in demand are prerequisites for the prevention of cerebral ischemia and neuronal dysfunction. This overview discusses age-related alterations in three main regulatory paradigms involved in the regulation of cerebral blood flow (CBF): cerebral autoregulation/myogenic constriction, endothelium-dependent vasomotor function and neurovascular coupling responses responsible for functional hyperemia. Pathophysiological consequences of cerebral microvascular dysregulation in aging are explored, including blood brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages, microvascular rarefaction and ischemic neuronal dysfunction and damage. Due to the widespread attention that VCID have captured in recent years the evidence for the causal role of cerebral microvascular dysregulation in cognitive decline is critically examined.

The guidelines for the diagnosis and treatment of novel coronavirus (2019-nCoV) infection (trial version 7

China Nhcotpsro

China NHCotPsRo. (2020). The guidelines for the diagnosis and treatment of novel coronavirus (2019-nCoV) infection (trial version 7) (in Chinese). http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4ce-f80dc7f5912eb1989/files/ce3e6945832a438eaae415350a8ce964.pdf.

Epidemiological and clinical characteristics of 99 cases of

Jan 2019

N Chen
M Zhou
X Dong
J Qu
F Gong
Y Han
Y Qiu
J Wang
Y Liu
Y Wei

Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., Qiu, Y., Wang, J., Liu, Y., Wei, Y., et al. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in

Figure 1 (Color online) A timeline of events for the notice of neurological manifestations in COVID-19 patients. Wuhan, China: a descriptive study

LANCET
507-513

Figure 1 (Color online) A timeline of events for the notice of neurological manifestations in COVID-19 patients. Wuhan, China: a descriptive study. Lancet 395, 507-513.

The brain, another potential target organ, needs early protection from SARS-CoV-2 neuroinvasion

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