- SARS-CoV-2 is a novel coronavirus that causes COVID-19 and primarily spreads through respiratory droplets. It attaches to human cells through ACE2 receptors and CD147 receptors. - Certain ACE2 receptor polymorphisms may increase or decrease susceptibility to SARS-CoV-2 infection. A recombinant soluble ACE2 protein is in clinical trials to treat COVID-19. - A CD147 antibody called meplazumab may effectively inhibit SARS-CoV-2 infection and cytokine storm, even against variants like Delta. Meplazumab works by blocking viral entry through ACE2 and CD147 receptors.

1. Title
SARS-CoV-2 Pathogenesis and Development of Therapeutic Strategies

2. Introduction
• SARS-CoV-2 is a noval corona that causes respiratory
illness COVID-19 pandemic.
• Its is believed to be transmitted from bats to humans due
to 96.2 % similarity to bat corona virus.
• First identified in Wuhan, China.
• The virus primarily spreads respiratory droplets.
• Incubation period is about 5–6 days, however it can take
up to 14 days.

3. Figure 1. Coronavirus Structure
• Medium-sized virus size, but largest mRNA genome
• Enveloped +ve stranded RNA
• mRNA encased in nucleocapsid
• Lipid Bilayer – Soap works to disrupt this!
• Corona = Crowns for Spikes
• Glycoprotein Spike
• Spikes allow it to attach to human cell receptors in upper or
lower airway
Coronavirus Structure

4. SARS-CoV-2 Attachment
ACE-2 Receptors
The viral spike (S) protein engages the human angiotensin-
converting enzyme 2 (ACE2) receptor to invade host cells with
~10–15-fold higher affinity compared to SARS-CoV S-protein,
making it highly infectious.
• Type 2 alveolar cells - highest
• Upper Intestinal epithelia
• Myocardial cells
• Kidney proximal tubule cells
Figure 2. A proposed model of the
mechanisms whereby coronavirus
SRA-CoV-2 enters cells
CD147: It also act as universal receptor for SAR-CoV-2 and great
role in SARS-CoV-2 Pathogenesis

5. Can ACE2 Receptor Polymorphisms can alter Host
Susceptibility to SARS-CoV-2 ?
• There exists ACE2 variants in human populations, that may
increase or decrease its affinity to SARS-CoV-2 S-protein
and thereby render individuals more resistant or susceptible
to the virus.
• To investigate this, we assessed ACE2 protein-altering
variations from a number of databases including gnomAD,
RotterdamStudy, and Asian-specific databases.
• We identified several ACE2 polymorphic variants that
increase ACE2/S-protein interaction including S19P, I21V,
E23K, K26R.
• We also found ACE2 variants having decreased binding
affinity for ACE2 include K31R, N33I, H34R. Figure 3. Enhancing And
Disruptive Variants

6. • To further understand the importance of the ACE2 variants in susceptibility, it will be important to
correlate clinical outcomes with ACE2 genotypes at population scale.
• ACE2 K26R, predicted to increase susceptibility to SARS-CoV-2, is found in 8 women and 6 men
in the UK Biobank exome sequencing data set.
• Individuals have this variant have 2.4-fold increased odds of infection compared to those who do
not carry the variants.
ACE2 Can Be Used As A Target In COVID-19 Therapy:
• Human recombinant soluble ACE2 is in clinical trials to treat SARS-CoV-2 infection
• Further a recombinant ACE2 protein can be engineered that can neutralize CoVs that may emerge
during future epidemics.

7. CD147 antibody specifically and effectively inhibit and
cytokine storm of SARS-CoV-2 and its variants delta, alpha,
beta, and gamma

8. Does Meplazumab (CD147 Antibody) block cellular
entry of SARS-CoV-2 and its variants?
• Sars-CoV-2 and its variants were made to infect ViroE6 cell lines.
• When the CD147 receptor was knocked out ,there was a decreased cellular entry reported not only
by SARS-CoV-2 but also, its variants including alpha, beta, gama and delta.
Fig.1: CD147 knockout and anti-CD147 antibody exhibit universal inhibition against SARS-CoV-2 and variants.

9. This clearly shows that CD147 is another receptor involved in
aiding cellular entry to SARS-CoV-2 and its variants.

10. hCD147 Transgenic Mouse Model study:
Hcd147 mice model exhibited:
• Cytokine storm
• Lung damage/pneumonia
This concludes that :
• HCD147 receptor plays role in not only cellular entry but also in pathogenesis like cytokine storm
and pneumonia
• HCD147 mice model is an excellend model to study SARS-CoV-2 as it exhibits all the symptoms
as the Coivd-19 patients.

11. CyPA plays role in causing CD147 related Cytokine storm in
SARS-CoV-2 infected patients:
• CyPA is cyclosporin A and is a protein secreted as a response to inflammatory stimuli.
• Lung epethilial cells were studied
• The spike protein CD147-CyPA is responsible for initiating the Covid-19 cytokine storm
• Further investigations on infected VeroE6 cell lines showed decreased expression of CyPA when
CD147 was knocked out and ACE2 was kept. However, when the CD147 was overexpressed, there
was increase in expression of Covid-19 induced CyPA as well
• The spike protein of SARS-Cov-2 when interacts with the CD147 receptor it initiates the JAK-
STAT pathway as a result of which there is an induced expression of CyPA. The CyPA then binds
to CD147 and initiate the MAPK pathway eventually mediating expression of cytokines and
chemokines.

12. Fig.2: CyPA protein detected in the plasma
of healthy donors (n = 100), COVID-19
patients with mild symptoms (n = 159) and
COVID-19 patients with severe/critical
symptoms (n = 106) by ELISA
Fig.3: The heatmap of 32 differential cytokines.
Fourty human cytokines were detected in plasma
from healthy individuals (n = 100) and COVID-19
patients (n = 200, including 41 severe/critical and
159 mild) using cytokine chips.

13. THERAPY????
MEPLAZUMAB
• After the identification of the pathogenesis, the therapy that can be a successful candidate is
Meplazumab.
• It is a CD147 antibody that has the ability to combat SARS-Cov-2 Virus.
• To verify this, further studies were carried out where the hCD147 mice models already infected
with Covid-19 were treated with Meplazumab.
• The usage of this drug against the alpha and beta variant showed significant decrease in virus
loading and the pneumonia was also improving.

14. Fig.4: Schematic diagram of CD147-CyPA regulation of cytokine
expression and blocking effect of Meplazumab

15. Working of Meplazumab
Meplazumab works by blocking the spike and CD147 receptor thereby reducing viral entry and also
the CyPA mediated cytokine storm. Both ACE2 receptor and CD147 receptor can synergistically be
targeted to stop the infection. Therefore, CD147 is a promising target for the treatment of COVID-19
caused by SARS-CoV-2 and its variants.

16. Tiny particle could make a powerful vaccine
• Messenger RNA (mRNA) vaccines and COVID-19 vaccines both employ nanoparticles. These
vaccinations include a strand of genetic code that contains instructions for making a coronavirus
protein. The protein is produced when cells take in this genetic code. When the immune system
recognises the protein, it begins to produce antibodies that aid in the battle against the coronavirus.
A COVID-19 infection can be fought off before it causes sickness once the body has built up an
army of antibodies.
• mRNA, on the other hand, is extremely fragile on its own. It would disintegrate if injected into the
body as a singa lipid nanoparticle to safeguard the genetic material.
• Lipids, such as oils and fats, are molecules that do not dissolve in water. A lipid nanoparticle is a
protective droplet that contains mRNA and won't disintegrate in body fluids. This nanodroplet
keeps the mRNA alive long enough to get it into the body's cells and start building proteins.

17. OBJECTIVE OF STUDY
Nanoparticles containing dozens of copies of a SARS-CoV-2 protein fragment could provide
protection against a wide range of coronaviruses.
EXPERIMENTALAPPORACHES:
• The University of Washington's David Veesler and Neil King, as well as their colleagues,
developed a vaccination that relies on a spike component known as the receptor binding domain
(RBD). They used nanometer-scale particles studded with dozens of RBDs to inject monkeys with
the vaccine, which produced virus-blocking ‘neutralising' antibodies against the Alpha, Beta, and
Gamma versions, as well as related animal coronaviruses. Clinical trials for this vaccine are
currently in phase III.
• The researchers also looked at nanoparticle vaccinations that contained RBDs from a variety of
sarbecoviruses, a coronavirus family that includes SARS-CoV-2. These vaccinations induced the
development of neutralising antibodies in mice.

18. IMMUNE RESPONSE
• As evidenced by several studies, nanoparticle interactions with biological systems can stimulate
inflammatory or allergic reactions and activate the complement system. Nanoparticles can also
stimulate immune response by acting as adjuvants or as haptens.Interection of nano vaccine with
immune response is shown in the fig.

19. Figure 01. Nanotechnologies utilized in
nanomedicine vaccines. Ag (antigen); Ab
(antibody); APC (antigen presenting cell); IgG
(serum immunoglobulin G); AFC (antibody
forming cell); ADCC (antibody-dependent
cytotoxic cell); Tc (cytotoxic T-cell); GC
(granulocyte); Th (helper T-cell); MAC
(macrophage); MC (memory cell); NKC (natural
killer cell)

20. Examples of NPs used in vaccinations.
Types of CoVs NPs Adjuants Finding
SARS-COV Gold NPs Gold NPs Stimulation of
igG response
MERS-CoV
(RBD antigen)
Ferritin-based
NPs --
Stimulation of
CD4+ T-cells
and IFN-γ
TNF-α
responses
MERS-CoV Spike protein
NPs
Aluminum Stimulation of
significant
titers of
neutralizing
antibody and
Th2 immune
response,
with no
stimulation of
Th1 immune
response

21. FUTURE GOALS OF STUDY
These findings pave the path for the development of a pan-sarbecovirus vaccination that could
protect against SARS-CoV-2 variations and sarbecoviruses that may in the future jump from animals
to people.

22. References
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SARS-CoV-2 and its variants delta, alpha, beta, and gamma. Sig Transduct Target Ther 6, 347 (2021).
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Somasekar, S., Hiranjith, G. H., … Seshagiri, S. (2021). Human ACE2 receptor polymorphisms and altered
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M. R., & Laurent, G. J. (2002). Angiotensin converting enzyme insertion/deletion polymorphism is associated with
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23. Thanks