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Page 142 Das et al. Neuroimmunol Neuroinflammation 2020;7:141-9 I http://dx.doi.org/10.20517/2347-8659.2020.36

In addition to their genetic homology, the pathology that the two viruses exhibit in the clinic are highly
[2]
similar . In a recent report from Wuhan, China, Mao and colleagues showed that in addition to respiratory
symptoms including pneumonia and acute respiratory distress syndrome (ARDS), out of 214 hospitalized
COVID-19 patients 78 (36.4%) showed neurological manifestations such as cerebrovascular diseases (5.7%),
[3]
impaired consciousness (14.8%), and skeletal muscle injury (19.3%) . Six percent of COVID-19 patients
[4]
have been reported to show symptoms of stroke and 15% were reported to show encephalopathy . A
number of symptoms such as dizziness, headache, loss of taste and smell, impaired consciousness, seizures,
and nerve pain suggest a neurological connection to this viral infection.

[5]
Previously, SARS-CoV was observed in the cerebrospinal fluid of a SARS patient showing ARDS .
Neuropathy in a COVID-19 patient has been reported in which the patient had hyposmia and altered
[6]
taste sensation . Establishing the link between prior coronaviruses and their neurotropism appears to be
important because there is now mounting evidence for SARS-CoV-2 neuronal abnormalities emerging as a
[7]
significant symptom associated with the disease . COVID-19 patients can show neurological manifestation
under three situations: due to neurotropism of the virus, post-infective neurological complications
or aggravated symptoms in patients with neurological co-morbidities like dementia . Moreover, the
[8]
neurological complications and symptoms can be central, including headache, dizziness, altered sensorium,
stroke, ataxia, encephalitis, and seizuers, or peripheral, like loss of smell or taste sensation or skeletal
[8]
muscle injury . Herein, we review a profound neurological basis of SARS-CoV-2 infection-induced global
pandemic and how the viral infection modulates the breathing of the lungs leading to fatal ARDS, to which
about 50%-80% of the severely ill patients succumb.

NEUROTROPISM OF β-CORONAVIRUSES
The family of β-coronaviruses, to which SARS and SARS-CoV-2 belong, have been extensively studied.
Several of the β-coronaviruses have been discovered within the brain (especially the brain stem), including
SARS-CoV, hCoV-229E, hCov-OC43, mouse hepatitis E, and porcine hemagglutinating encephalomyelitis
[5,9]
(HEV) coronavirus . Middle Eastern respiratory syndrome (MERS) virus, another notable zoonotic viral
outbreak in 2008-2009, that utilizes a different host receptor, DPP4, has also been discovered in the brain
stem of experimental animals even in the absence of lung infection , demonstrating a strong propensity
[10]
for the family of β-coronaviridae to infect the brain. While ACE2 is expressed at low levels within the
brain, it has been hypothesized that the “promiscuous” spike protein of β-coronaviruses may also have an
[10]
unknown receptor in the brain and peripheral nerves to which the neurotropism is owed .

SARS-CoV and MERS-CoV are considered important coronaviruses with the potential of nervous system

damage. SARS-CoV was found to cause neur ological conditions like demyelination of nerve fibers,

ischemic changes of neurons, and diseases such as encephalitis, polyneuropathy, and aortic ischemic
[11]
stroke . Similarly, 1 in 5 MERS-CoV patients were reported with neurological symptoms such as paralysis,
[12]
ischemic stroke, loss of consciousness and Guillain Barré syndrome . The presence of SARS-CoV has also
been demonstrated in mice brain experimentally infected with SARS-CoV . Another coronavirus, the
[13]
mouse hepatitis virus type 3, can disrupt the BBB by down-regulating interferon β which would allow virus
[14]
and infected immune cells in .
NEURAL CONTROL OF BREATHING
The major life-threatening symptoms of SARS-CoV-2 infection are respiratory failure and pneumonia.
While pneumonia is largely an inflammatory condition of the lungs, breathing is extensively regulated by
the brain. Breathing is regulated by numerous internal and external stimuli, which are integrated in the
brain stem to produce the muscle movements necessary for inspiration (or inhalation), and expiration
(or exhalation) [Figure 1A]. The rate and phases of the breathing pattern arise from respiratory centers