There are two main processes
that drive the pathogenesis
of infection by SARS-Coronavirus II or COVID-19.
The first, is the early infection,
this is driven by actual attack
of the virus on its target cells
and replication within those cells.
However, a secondary process a later infection
or perhaps more accurately
named, “Later inflammation,”
is an exaggerated immune or inflammatory response,
to that viral infection that
further results in tissue damage
or innocent bystander damage
by the human immune system.
Typically, after exposure to the virus
as you see here, the SARS-Coronavirus II,
it will bind to its target cell and then its RNA,
will become internalized.
There are two methods to enter the cell,
either through membrane fusion
and insertion of the virion or by endocytosis,
if the cell has the ability to perform this act.
After endocytosis, the RNA is internalized
and undergoes translation
and transcription process,
to both create more RNA for new virions,
as well as then a synthesis of viral proteins,
the four proteins discussed in another lecture,
so that then the virus can be
assembled within the cytoplasm
of its target cell and then be
released through a mechanism,
which, remains to be determined.
The membrane fusion, typically occurs,
through binding of the spike protein
or the S-Protein of the SARS-Coronavirus II,
to the ACE-2 receptor.
The SARS-Coronavirus II’s spike
protein specifically recognizes
and binds tightly to
angiotensin-converting enzyme 2,
now known as, the ACE-2 receptor for the virus.
After that initial binding
then proteolytic cleavage
of the S or spike protein must
occur via host cell proteases,
especially TMPRss2 and that is
essential to allow that viral membrane,
to fuse with its target cells membrane.
ACE-2, angiotensin-converting enzyme 2,
is expressed robustly throughout the human body,
especially by epithelial cells in a blood vessel,
so, so-called endothelial cells,
but also expressed by type
II pneumocytes, in the lungs,
elsewhere in the kidney, the intestine et cetera.
So, after the coronavirus
enters into its host cell,
via binding to the ACE-2 receptor or enzyme,
the receptor the ACE-2 receptor is internalized
and then is followed by a secondary
inhibition of further ACE-2,
expression by the target host cell membrane.
This release causes then ADAM17 gene expression,
which, subsequently releases
tumor necrosis factor,
alpha and cytokines, so
especially such as the interleukins
like 1 and 6 and then interferon gamma.
This, sets up then a vicious
cycle of further ACE-2 inhibition,
further gene expression, further
release of pro-inflammatory cytokines
and so eventually one can drive a cytokine storm.
High levels of ACE-2 expression,
so, again receptors, for the virus itself
are associated with pre-existing comorbidities,
especially chronic cardiovascular disease
and these individuals have a much
higher risk of severe COVID-19.
There are other comorbidities as well,
that have been identified clinically for example,
individuals with insulin
dependent diabetes, mellitus,
individuals with hypertension and it may be,
that these individuals also
express higher levels of ACE-2,
putting them at further
risk of more viral binding.
What happens when ACE-2 is
down regulated or suppressed?
Well ACE-2 itself is a negative regulator,
of the renin-angiotensin-aldosterone
system or the are the (RAAS) system
and if it is down regulated by
viral binding that negatively
or directly affects cardiovascular function.
Also, ACE-2 has a protective role
in epithelial cells in the lungs,
especially in the alveola
and reducing its expression,
will lead to alveolar cell damage.
Of course, we know, COVID-19, is
primarily a respiratory illness
and you can start to understand, why,
when the target of opportunity of
course is ACE-2 down regulation
and allowing alveolar cell damage.
So, let's go through a typical immune response
and this is not unique to
SARS-Coronavirus II infection,
this is how the human body's
adaptive immune system responds
to any antigenic challenge,
any exposure to not self.
The adaptive immune response,
starts with recognition and binding
or opsonization if you will,
of the antigen, in this case, SARS-Coronavirus II,
by antigen presenting cells, “APC’s,”
and these are macrophages dendritic
cells and some epithelial cells,
all of which are accompanied by cytokine release.
After ingestion of that antigen,
the antigen presenting cell,
then expresses the antigen at its cell surface
in combination with MHC classes I and II
to a T-lymphocyte a T-cell such as you see here,
binding to the T-cell receptor the TCR.
Although there are many subsets of T-lymphocytes,
the two that we're focusing on here,
are the biggest categories the CD4+
T-lymphocytes or T-helper lymphocytes
and the CD8+ or cytotoxic T lymphocytes.
These, are then activated followed by binding
or perhaps concurrently by binding
of the antigen presenting cell,
with the B-lymphocyte.
The B-lymphocytes interactions
with the CD4 T-helper,
T-lymphocytes, then allows
formation of antibodies,
all uniquely specific to the initial antigen,
expressed by the antigen presenting cell,
again, in this case, SARS-Coronavirus II
and most often the spike protein,
since that is the most easily accessible antigen,
which is recognized by the
antigen presenting cells.
B-lymphocytes, will produce antibodies
and a small subset of those
will then, mortalize, into
what are called “Memory cells,”
and this is one of the joys or the
benefits of the adaptive immune response.
It remembers its response so it can reactivate
and escalate should there be a new
challenge to that same antigen.
So, how does all this look then
and the more macroscopic level?
Again, as we, as humans, inhale and
or are exposed to SARS-Coronavirus II,
we enter the virus into our lungs,
were it finds its way to ACE-2,
expressing alveoli, in
epithelial cells in the alveolus
and there, that cycle, we just discussed,
can precipitate a cytokine storm.
This, allows for leakage of
fluid, of red blood cells,
of further phagocytes such as
neutrophils and macrophages,
into the alveolar space and eventually,
as this immune cytokine
storm-based response develops,
the alveolus floods and it is unable
to allow for normal ventilation
and perfusion and thus gas
exchange does not occur.
This as we know leads to the shortness of breath
and the respiratory failure,
which, so typifies severe COVID-19.