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directly or indirectly to motor neurons which innervate the diaphragm, intercostals, and airway muscles
[Figure 1A]. Rhythmic limb movement has also been shown to modulate breathing through afferent
[18]
sensory pathways . Of particular interest are vagal sensory neurons expressing chemoreceptors and
[19]
mechanoreceptors, which project from the lungs and airways to respiratory centers of the brainstem .
Due to their inherent proximity to the primary infection site, these sensory neurons present one potential
[20]
mechanism by which respiratory viruses may enter the brain . Expiration is passive at rest. However,
[21]
active expiration may be brought on by increased O demand, such as respiratory distress . Disinhibition
2
or activation of neurons in the lateral parafacial nucleus (pF ), which project to expiratory premotor
L
[22]
neurons, causes contraction of muscles, which reduces lung volume below their resting capacity . This
reduced lung volume after active exhalation increases the volume of the subsequent breath resulting in
greater O delivery. A third phase, post-inspiration, may occur between the inspiration and exhalation
2
[23]
phases. Post-inspiration is a delay of lung deflation which increases gas exchange in the lung . It may
originate from interneurons medial to the parafacial nucleus, referred to as the post-inspiratory complex
[24]
(PiCo) . Thus, infection of any of these regions of the brain may lead to respiratory distress or even
failure.
EVIDENCE OF NEUROTROPISM OF SARS-COV-2
It has been postulated that, like other β coronaviruses, SARS-CoV-2 can also infect the brain by migrating
[5]
from the general circulation to the cerebral microcirculation via endothelial cells which express ACE2 .
[25]
In a recent case study published by Poyiadji et al. , they described an acute hemorrhagic necrotizing
encephalopathy that was directly attributed to SARS-CoV-2 infection and the concurrent cytokine storm
induced upon infection [25,26] . Beyond isolated cases of overt severe neurological pathologies, 45% of severe
cases exhibited neurologic symptoms , increasing the likelihood that potential complications arising from
[3]
severe SARS-CoV-2 infections may have a strong neurologic component that has yet to be described and
characterized. Human coronavirus OC43 has been demonstrated to be transmitted in mice both passive
[27]
diffusion of released viral particles and axonal transport .

Possible pathways for SARS-CoV-2 invasion of the central nervous system
The major receptor for SARS-CoV-2, ACE2, is distributed in multiple tissues of the body. It is present
in epithelial cells of alveoli and small intestine arterial and venous endothelial cells and arterial smooth
muscle cells neuronal, glial and endothelial cells of the brain . Low expression is observed in
[5]
[28]
glomerular tubular cells. Glomerular endothelial cells, Kupffer cells, hepatocytes, spleen, thymus, lymph
[29]
nodes and immune cells do not show the expression of ACE2 . Similar to SARS-CoV, SARS-CoV-2
uses the spike protein S1 to attach to the host cell ACE2 receptor [13,30] , but SARS-CoV-2 binds to the
receptor with 10-20 fold higher affinity . A possible explanation for this increased affinity comes from
[30]
[31]
the intense work of Shang et al. . By determining the crystal structure of the receptor-binding domain
(RBD) of the spike protein (S1), they showed that, compared to SARS-CoV, SARS-CoV-2 receptor
binding motif (RBM) contains a structural change in the ACE2-binding ridge caused by a four residue
motif (residues 482-485: Gly-Val-Glu-Gly) due to which the ridge becomes more compact and forms
[31]
more rigid contact with the N-terminal helix of ACE2 . In addition, changes in several other residues
in the SARS-CoV-2 RBD caused higher stabilization of two virus-binding hotspots at the RBD-ACE2
[31]
interface causing higher affinity of SARS-CoV-2 to ACE2 . A comparison between SARS-CoV-2 RBD
subdomain-1 (S1) with the RBD glycoprotein of bat coronavirus (RaTG13) and S1 protein of SARS
coronavirus showed strong but not identical homology in the spike proteins of all three CoVs which
[5]
[32]
can possibly explain the high binding affinity of SARS-CoV-2 to human ACE2 receptor . Ou et al.
showed that the SARS-CoV-2 spike protein is less thermostable than SARS-CoV spike protein, suggesting
[32]
its higher infectivity .Upon binding with the ACE2, SARS-CoV-2 S protein is primed by serine protease
[33]
TMPRSS2 . SARS-CoV-2 might be able to transmigrate to the brain via the general circulation, the