Figure 1.
Hypothesis of involvement of free S1 subunits of SARS-CoV-2 spike
protein into COVID-19 induced
Binding to the receptor via their intact RBDs these molecules may induce
ACE2 downregulation and the downstream deleterious effects as it was
suggested by (Gheblawi et al., 2020; Verdecchia, Cavallini, Spanevello
& Angeli, 2020).
If our hypothesis turns true, the release of free S1 particles from the
infected cells and virions should reduce the virus infectivity towards
the cells neighboring to the infected cells. Therefore, two stages of
the SARS-CoV2 infection in the lungs can be predicted:
- The virus infects certain loci where the production of free S1 protein
causes the downregulation of ACE2 in the non-infected cells in the
proximity of the viruse-infected cells. Simultaneously the expression
of ACE2 on more distant cells, that did not yet encountered S1
particles, can be increases due to the effect of interferon produced
in the infected cells that has been shown to stimulate ACE2 expression
(Ziegler et al., 2020). The local disbalance of the angiotensin II/
angiotensisn (1-7) levels also may elicit compensatory ACE2 increase
in the cells not yet affected by the virus (though such compensatory
circuit is not yet described, it would be logical to suggest it may
exist). Therefore, the virus spread for longer distances (e.g. to
another alveoles) would be facilitated, however the virus induced
tissue damage would be limited.
- When larger amount of the tissue is infected, the greater quantities
of free S1 is produced, and the RAS disbalance on the organ or
organism level is induced. This causes the deleterious effects such as
increased inflammation, thrombosis and pulmonary damage as it was
suggested previously (Gheblawi et al., 2020; Verdecchia, Cavallini,
Spanevello & Angeli, 2020). Simultaneously the virus production
should be decreased due to downregulation of ACE2 production in the
infected areas of the lungs.
This model corresponds well to the known clinical traits of COVID-19
(Siordia, 2020; Zhao et al., 2020): involvement of large areas of the
lungs with frequent bi-lateral pneumonia (stages I of our model),
reported relatively good patients state despite significant part of the
lungs involved according to radiological examination data that is
followed by abrupt deterioration of the patients conditions in next
hours or days (late stage I and stage II).
The proposed model suggests that the clinical interventions suggested to
maintain RAS balance (Sriram & Insel, 2020) should have synergistic
effect with protease inhibitors, specially with furin inhibitors.
Although the in vitro data suggest that lack of the furin
pre-processing of SARS-CoV-2 S protein can be compensated by the
post-attachment processing by other proteases (Shang et al., 2020), our
model suggests that furin inhibition will not only decrease the virus
infectivity but will also decrease the shed of the free S1 particles
from both virions and infected cells and blunt the infection effect over
RAS.
It also should be mentioned that free S1 molecules may represent a
target for COVID-19 therapy or prevention. After the separation of S1
subunit from S2 stem the potential epitopes free of the glycans
shielding the external surface of the complete S protein13 become exposed. So the immunization by the
recombinant proteins that would elicit the antibodies response against
these conserved and unprotected epitopes may lead to the sequestration
of free S1 molecules to immune complexes and their elimination thus
reducing the probability of severe COVID-19 pneumonia.