A Broad Understanding of SARS-CoV-2

Sarah Jones
Introduction
SARS-CoV-2 is a highly pathogenic virus belonging to the beta-CoV genera. The virus is
similar to other coronaviruses like SARS-CoV and MERS-CoV, which are all enveloped in
structure and single stranded, positive sense RNA viruses. They are also all zoonotic and thought
to originate in bats, being transmitted to humans through intermediate species then from human
to human afterwards. The intermediate species for SARS-CoV-2 is still unknown. The similarity
of these viruses has shown to be useful to understanding this novel coronavirus, and the S
proteins of SARS-CoV and SARS-CoV-2 even share approximately 75% amino acid sequence
identity. While all of these viruses are known to be rapid in transmission and quite virulent, the
novel coronavirus, SARS-CoV-2, is the source of the 2020 COVID-19 global pandemic.

Virology
The spike protein, or S protein, of coronaviruses like SARS-CoV-2 plays an essential role
in infection by mediating viral entry and fusion to target cells. For SARS-CoV-2, the virus
interacts with the human cell receptor ACE2; specifically, the interaction takes places between
the receptor binding domain (RBD) of the virus and the N-terminal peptidase domain (PD) of
ACE2, with only one PD being able to interact with one RBD. The efficacy of the viral entry is
largely based on the strength of this interaction, which can be varied depending on the
conformation the RBD takes, considering the S protein is trimeric and can exist in both up and
down conformations. For proper binding, the up conformation is necessary as it avoids steric
clash. More specifically, the S protein is divided into S1 and S2 subunits and has two cleavage
sites: the S1/S2 and S2’ sites. The S1 subunit contains the N-terminal, N-terminal domain,
receptor binding domain, and receptor binding motif, and is primarily responsible for receptor
binding, which allows for shape changes to take place that enable S2 subunit-driven viral
membrane fusion and entry. The S2 subunit is able to do this as it has a transmembrane domain,
cytoplasmic domain, fusion peptide, and heptad repeat 1 and 2. These heptad repeats make up
the 6-HB fusion core and are essential for this viral membrane fusion. While these subunits act to
allow infection, priming by host cell proteases is essential for proper viral entry. First, furin
cleaves the S1/S2 site, then TMPRSS2 cleaves the S2’ site. Cathepsin B and L are also thought
to aid in the priming process, but they are not essential like the other proteases. Once the virus
enters the target cell, it has the ability to create viral proteins and replicate and can trigger
immunologic reactions involved in the COVID-19 disease.

Epidemiology
SARS-CoV targets pneumocytes and lung macrophages as they express ACE2 at high
levels, so SARS-CoV-2 is thought to have similar target cells for infection. More specifically,
SARS-CoV-2 infects cells with the highest ACE2, TMPRSS2, and furin expression, with ACE2
being the limiting factor in most cases. Within the lung tissue, ACE2 expression is highest in
AT2 cells, and in subsegmental bronchial branches, in transient secretory cells. These cells are
thus the most vulnerable to infection, and double or triple positive cells for ACE2, TMPRSS2,
and furin are even more so. However, the cells with highest ACE2 expression are nasal secretory
cells, and this matches with the data that nasal swabs of COVID-19 patients contain higher viral
loads than throat swabs. Nasal secretory cells are further divided into two clusters of goblet cells
and one of ciliated cells and are responsible for viral transmission from human to human via
droplets, acting as both a portal for infection and perhaps the primary source of viral
transmission. While droplets are the main transmission route, transmission can also take place
when humans come in contact with infected surfaces.

Disease
COVID-19, the disease caused by SARS-CoV-2, involves damage to the respiratory tract
and lungs. Infection is often associated with pneumonia or related illness, and the primary
symptoms are cough and fever. Other common symptoms include shortness of breath and sore
throat. There is no correlation between sex, age, history, and infection incidence, but the disease
may impact people of certain categories more so than others and can lead to fatality. The
mechanisms behind the damage caused from the disease are not entirely understood, but are
thought to be due to inflammation by the immune system in response to viral infection. A
cytokine storm may be causing lung injuries. This is supported by data showing that patients
infected with SARS-CoV-2 exhibit higher levels of cytokine and chemokine secretion, and these
levels rise even more with ICU patients. Some theories as to how this inflammation response
takes place include mass cell apoptosis, downregulation of ACE2 by SARS-CoV-2, and antibody
response related to anti-spike protein IgGs.

Immunology
There is little development or knowledge about SARS-CoV-2 neutralizing antibodies, but
information about SARS-CoV and MERS-CoV neutralizing antibodies could be helpful. For
these human coronaviruses, the neutralizing antibodies primarily target the RBD of the S protein,
so it is highly possible the same occurs with antibodies related to SARS-CoV-2. One SARS-CoV
neutralizing antibody, CR3022, has even been found to interact and bind with the S protein of
SARS-CoV-2. However, while CR3022 effectively neutralizes SARS-CoV by binding to the
RBD without blocking the ACE2 binding site, it has not been found to effectively neutralize
SARS-CoV-2 yet even though the interaction mechanism is similar.
Besides natural neutralizing antibodies, many drugs have been tested against
SARS-CoV-2 to look for inhibition of entry or replication. One target is TMPRSS2, the protease
responsible for essential priming of the S protein and thus viral entry. Aprotinin and camostat
mesylate have both been found to act as effective inhibitors against TMPRSS2 and show
promising results for slowing viral entry and replication. E64d can effectively block cathepsin B
and L, which also aids in suppressing the virus, even though these cathepsins are not essential for
priming. 6-HB interactions in the S2 subunit have also been blocked by EK1 protein, and this
protein shows higher efficacy at inhibiting the virus when bound to cholesterol; out of all
lipopeptides synthesized in a study, EK1C4 showed to be most potent. Overall, primary drug
targets are currently proteins that interact with the S protein of the virus as inhibiting them can
inhibit viral entry by blocking priming and binding to the receptor.

Conclusion
SARS-CoV-2, a novel coronavirus, has much shared identity with other human
coronaviruses-- especially SARS-CoV, and infects humans primarily via respiratory and nasal
droplets containing the virus but also through contact with infected surfaces. Once inside the
body, the virus targets cells within the respiratory tract as they have the highest expression of the
receptor ACE2 as ACE2 interaction with the S protein of the virus is essential for viral entry and
membrane fusion. The S protein accomplishes this through shape changes that occur in the two
subunits thanks to host cell proteases TMPRSS2 and furin that cleave at specific sites, effectively
priming the protein for proper binding to the receptor. Due to this essential activity of the host
cell proteases, they are targets for many drugs being tested to inhibit SARS-CoV-2 infection and
replication among other proteases and components of the S protein itself. Neutralizing antibodies
may also be useful in fighting infection, but no SARS-CoV-2-specific neutralizing antibodies
have been identified as of yet. Once infected with the virus, the human body exhibits an
inflammatory immunologic response that may cause damage to the body, especially the lungs via
an unknown mechanism. The disease from infection, COVID-19, is associated with this lung
tissue damage and even fatality, with primary symptoms being fever and cough.
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