AlooDenish

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•  
• SARS-CoV-2 and COVID-19
• A presentation by
• Aloo Denish
• (Biochemist Microbiologist)
• Chuka University CSI International Ltd
• E-mail aloo.denish3_at_gmail.com
• ... if you know your enemies and know yourself,
  you will not be imperiled in a hundred battles.
  Sun Tzu, The Art of War

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1.0 History - Did you Know?

• In the past, the world has faced respiratory
  disease pandemics
• The 1918 H1N1 (Spanish flu) -50 million deaths
  worldwide
• The 1957 H2N2 (Asian flu) -14 million deaths
  worldwide
• The 1968 H3N2 (Hong Kong flu) -14 million deaths
  worldwide
• The 2005 H5N1 (Bird flu)
• The 2009 H1N1 (Swine flu)- 151,700575,400 deaths
  worldwide
• 2001 to 2003 severe acute respiratory syndrome
  (SARS)
• 2012 to 2015 Middle East respiratory syndrome
  (MERS)
• December 2019 Novel coronavirus 2019
  (SARS-CoV-2) that causes Covid-19 discovered in
  Wuhan city, Hubei Province, China

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2.0 Definition

• Coronaviruses (CoVs) are enveloped,
  positive-sense, single-stranded RNA viruses that
  belong to the subfamily Coronavirinae, family
  Coronavirdiae, order Nidovirales.
• There are four genera of CoVs, namely,
  Alphacoronavirus (aCoV), Betacoronavirus (ßCoV),
  Deltacoronavirus (dCoV), and Gammacoronavirus
  (?CoV)
• Severe acute respiratory syndrome coronavirus 2
  (SARS-CoV-2) is the virus that causes COVID-19
  (coronavirus disease 2019), the respiratory
  illness responsible for the COVID-19
• Coronavirus disease (COVID-19) is an infectious
  disease caused by the SARS-CoV-2 virus.

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3.0 Taxonomy of SARS-CoV-2

• (unranked) Virus
• Realm Riboviria
• Kingdom Orthornavirae
• Phylum Pisuviricota
• Class Pisoniviricetes
• Order Nidovirales
• Family Coronaviridae
• Genus Betacoronavirus
• Subgenus Sarbecovirus
• Species Severe acute respiratory
  syndromerelated coronavirus
• Virus Severe acute respiratory syndrome
  coronavirus 2

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3.1 Variants of SARS-CoV-2

• There are many thousands of variants of
  SARS-CoV-2, which can be grouped into the much
  larger clades.
• The World Health Organization has currently
  (2021) declared four variants of concern, with
  evidence of increased transmissibility and
  virulence, alongside changes to antigenicity,
  which are as follows
• Alpha Lineage B.1.1.7 emerged in the United
  Kingdom in September 2020. Notable mutations
  include N501Y and P681H. An E484K mutation in
  some lineage B.1.1.7 virions has been noted
• Beta Lineage B.1.351 emerged in South Africa in
  May 2020. Notable mutations include K417N, E484K
  and N501Y.
• Gamma Lineage P.1 emerged in Brazil in November
  2020. Notable mutations also include K417N, E484K
  and N501Y.
• Delta Lineage B.1.617.2 emerged in India in
  October 2020.
• Other variants include Lambda (lineage C.37), Mu
  (lineage B.1.621), Epsilon (lineages B.1.429,
  B.1.427, CAL.20C), Zeta (lineage P.2), Theta
  (lineage P.3), Eta (lineage B.1.525), Iota
  (lineage B.1.526), Kappa (lineage B.1.617.1),
  e.t.c.

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4.0 Structure of SARS-CoV-2

• Spherical, enveloped, around 80120 nm in
  diameter, with multiple outwardly projected
  club-like homotrimeric, glycosylated S proteins
  imparting them incredible appearance of a solar
  corona, prompting their popular name, CoVs.
• Enclosed within the lipid bilayer envelope of the
  virion is helically symmetrical nucleocapsids
  comprising complex of ssRNA and capsid proteins.
  
• There are four important structural
  proteinsspike (S), membrane (M), envelope (E),
  and nucleocapsid (N) proteinsthat are encoded by
  structural genes located within the region
  preceeding 30 end of genome.
• There are several non-structural and accessory
  proteins, which together are responsible for the
  structural and functional aspects of virus

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5.0 Genome Organization

• SARS-CoV-2 is a positive-sense single-stranded
  RNA (ssRNA) virus, with a single linear RNA
  segment.
• Genome size ranges from 26 to 32 kb and comprise
  611 open reading frames (ORFs) encoding 9680
  amino acid polyproteins (Guo et al. 2020).
• Genome has highest composition of U (32.2),
  followed by A (29.9), and a similar composition
  of G (19.6) and C (18.3). The nucleotide bias
  arises from the mutation of guanines and
  cytosines to adenosines and uracils,
  respectively.
• The first ORF (ORF1a and ORF1b) comprises
  approximately 67 of the genome that encodes 16
  non-structural proteins (nsps), whereas the
  remaining ORFs encode for accessory proteins and
  structural proteins.
• Accessory genes are interspersed between the
  structural genes and contain at least nine ORFs
  for accessory proteins.
• Its genome lacks the hemagglutinin-esterase gene.
  However, it comprises two flanking untranslated
  regions (UTRs) at 5' end of 265 and 3' end of 358
  nucleotides.

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6.0 Description of Structural Organization

• Non-structural proteins
• Structural Proteins
• Accessory proteins

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6.1 Non-structural proteins

• The initial two-thirds of the RNA sequence encode
  the two main transcriptional units, ORF1a and
  ORF1ab these units encode two polyproteins (PP1a
  and PP1ab, respectively).
• The pp1a non-structural protein corresponds to
  NSP1 to NSP11 and pp1ab non-structural protein
  comprises of NSP12 to NSP16
• The larger unit, PP1ab, contains ORFs for at
  least 16 non-structural proteins (Nsp1-16)
• The non-structural proteins have various
  functions in biological phenomena that are
  important for the virus such as replication,
  correction of replication errors
  (proofreading), translation, suppression of
  host proteins, immune response blockage, and RNA
  stabilization.

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S.No Name Protein (Full Name) and function
1 nsp1 N-terminal product of the viral replicase -gt acts as host translation inhibitor and also degrade host mRNAs
2 nsp2 N-terminal product -gtBinds to prohibitin 1 and prohibitin 2 (PHB1 and PHB2)
3 nsp3 Papain-like proteinase -gt Responsible for release of NSP1, NSP2, and NSP3 from the N-terminal region of pp1a and 1ab
4 nsp4 Membrane-spanning protein containing Transmembrane domain 2 -gtInvolves in double-membrane vesicle formation
5 nsp5 Proteinase and main proteinase -gtInhibits IFNsignaling
6 nsp6 Putative transmembrane domain -gtInduces formation of ER-derived autophagosomes
7 nsp7 RNA-dependent RNA polymerase - Acts as a cofactor with nsp8 and nsp12
8 nsp8 Multimeric RNA polymerase replicase single-stranded -gtMakes heterodimer with NSP8 and 12
9 nsp9 RNA-binding viral protein -gtInvolves in dimerization and RNA binding
10 nsp10 Growth-factor-like protein possessing two zinc binding motifs -gtacts as a scaffold protein for nsp14 and nsp16
11 nsp11 short peptide at the end of orf1a -gt Unclear function
12 nsp12 RNA-dependent RNA polymerase gtfor replication and methylation
13 nsp13 Helicase -gt Helicase core domain binds ATP. Zinc-binding domain is involved in replication and transcription
14 nsp14 Exoribonuclease domain (ExoN/nsp14) -gtExoribonuclease activity and N7-guanine methyltransferase activity
15 nsp15 EndoRNAse nsp15-A1 and nsp15B-NendoU -gt Mn(2 )-dependent endoribonuclease activity
16 nsp16 2-O-MT 2-O-ribose methyltransferase -gtmediates mRNA cap 20-O-ribose methylation
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6.2 Structural Proteins

• The structural genes encode the structural
  proteins, spike (S), envelope (E), membrane (M),
  and nucleocapsid (N).
• 6.2.1 The S protein
• The total length of SARS-CoV-2 S is 1273 aa and
  consists of a signal peptide (amino acids 113)
  located at the N-terminus, the S1 subunit (14685
  residues), and the S2 subunit (6861273 residues)
• The S1 subunit and S2 subunit are responsible for
  receptor binding and membrane fusion,
  respectively.
• The S1 subunit comprises an N-terminal domain
  (14305 residues) and a receptor-binding domain
  (RBD, 319541 residues).
• The S2 subunit comprises the fusion peptide (FP)
  (788806 residues), heptapeptide repeat sequence
  1 (HR1) (912984 residues), HR2 (11631213
  residues), TM domain (12131237 residues), and
  cytoplasm domain (12371273 residues).
• SARS-CoV-2 S harbors a furin cleavage site
  (682685 residues) at the S1/S2 boundary, which
  may increase the efficiency of SARS-CoV-2
  transmission

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• 6.2.2 Envelope (E) protein
• The smallest amongst all the structural proteins,
  around 812 kDa.
• Function plays major role in pathogenesis,
  virus assembly, and release .
• 6.2.3 Membrane (M) protein
• n is O-linked glycoprotein of around 2530 kDa,
  and is most abundant amongst various structural
  proteins, and possesses three distinct
  transmembrane domains .
• The homodimeric M protein associates with other
  viral structural proteins, including
  nucleocapsid, facilitating the molecular assembly
  of virus particles as well as may be involved
  during pathogenesis.
• 6.2.4 Nucleocapsid (N) protein
• It distinctly possesses three highly conserved
  domains an N-terminal domain, an RNA-binding
  domain or a linker region, and a C-terminal
  domain.
• It has been observed that these three domains
  may together orchestrate RNA binding and its
  phosphorylated status is prerequisite for
  triggering a structural dynamism facilitating the
  affinity for viral versus non-viral RNA .
• Participates in RNA packaging in a
  beads-on-a-string type conformation. In addition
  to be involved in organization of viral genome, N
  protein also facilitates virion assembly and
  enhances virus transcription efficiency amongst
  others

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6.3 Accessory Factors

• There are nine accessory proteinsORF3a, 3d, 6,
  7a, 7b, 8, 9b, 14, and 10produced from at least
  five ORFs encoding accessory genes (ORF3a, ORF6,
  ORF7a, ORF7b, and ORF8), novel overlapping ORF3d
  (earlier known as 3b), leaky scanning of sgRNA of
  N gene (ORF9b and 14), and ORF10 from downstream
  of N gene.
• Accessory proteins play a crucial role in virus
  replication
• They may also be involved in host immune escape.
• these proteins play an important role in
  interactions between the virus and host,
  including modulating and blocking the production
  of pro-inflammatory cytokines

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• 6.3.1 ORF3a and ORF3d Proteins
• Accessory factor 3a is encoded by ORF3a located
  in between the S and E genes, and is the largest
  accessory proteins of SARS-CoV-2, consisting of
  274 amino acid residues.
• ORF3a forms dimer and its six transmembrane
  helices together create ion channelin the host
  cell membrane, which is highly conducive for
  Ca2/K cations compared to Na ion. It is also
  involved in virus release, apoptosis and
  pathogenesis.
• ORF3d encodes 3d protein which consists of
  154-aa long polypeptide chain, and is found to be
  located in the nucleolus and mitochondria.
• 6.3.2 ORF6 Protein
• A 61-amino acid long membrane-associated protein.

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• 6.3.3 ORF7a and ORF7b Proteins
• Synthesized from the bicistronic subgenomic RNA 7
  of SARS-CoV-2.
• The 122-aa ORF7a protein is a type-I
  transmembrane protein containing a 15 aa signal
  peptide sequence, an 81aa luminal domain, 21aa
  transmembrane domain and a short C-terminal tail.
• The ORF7b protein consists of 44-amino acids, and
  is an integral membrane protein, expressed in
  SARS-CoV-infected cells wherein it remains
  localized in the Golgi compartment
• 6.3.4 ORF8 Protein
• Consists of 121 amino acid residues.
• Has been found to interact with major
  histocompatibility complex-I (MHC-I), thereby
  mediating their degradation in cell culture, and
  therefore may help in immune evasion

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• 6.3.5 ORF9b Protein
• Consists of 97 amino acid residues, and is
  probably expressed by leaky scanning of sgRNA of
  N gene.
• Tends to associate with adaptor protein, TOM70,
  and therby suppress IFN-I mediated antiviral
  response
• 6.3.6 ORF10 Protein
• Encoding by gene predicted to be located
  downstream of the N gene
• 6.3.7 ORF14 Protein
• Made up of 73 amino acid residues, and is also
  likely to be synthesized by leaky scanning of
  sgRNA of N gene. However, its function is not
  clearly understood.

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7.0 Mutations

• Mutation on the spike protein -Mutation
  23403AgtG-(D614G)
• Mutation on the NSP12 protein -Mutation
  14408CgtT-(P323L)
• Mutation on the ORF3a protein -Mutation
  25563GgtT-(Q57H)
• Mutation on the NSP2 protein -mutation
  1059CgtT-(T85I)
• Mutations on the NSP13 protein
• Mutations on the ORF8 protein -two high-frequency
  mutations, 28144TgtC-(L84S) and 27964CgtT-(S24L)
• Mutations on the nucleocapsid protein -high
  frequency mutations, 28881GgtA, 28881GgtA, and
  28883GgtC.

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8.0 Life Cycle of SARS-CoV-2

• Involves cellular invasion of virus, expression
  of viral genes, and formation of progeny and
  eventual exit.
• Involves
• Attachment to Host Cell Surface, Penetration and
  Uncoating
• Replication-Transcription Complex (RTC)
  Formation
• Synthesis of Viral RNA
• Molecular Assembly and Release of SARS-CoV-2

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8.1 Attachment to Host Cell Surface,
Penetration and Uncoating.

• The spike (S) protein, via its receptor binding
  domain (RBD), attaches to angiotensin converting
  enzyme 2 (ACE2) receptors that is found on the
  surface of many human cells, including those in
  the lungs allowing virus entry.
• The S protein is subjected to proteolytic
  cleavages by host proteases (i.e. trypsin and
  furin), in two sites located at the boundary
  between the S1 and S2 subunits (S1/S2 site).
• In a later stage happens the cleavage of the S2
  domain (S2'site) in order to release the fusion
  peptide. This event will trigger the activation
  of the membrane fusion mechanism. Typically,
  human cell ingests the virus in a process called
  endocytosis

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• Once entered the cytoplasm, it has been suggested
  most likely that COVID-19 employs a unique
  three-step method for membrane fusion, involving
  receptor-binding and induced conformational
  changes in Spike (S) glycoprotein followed by
  cathepsin L proteolysis through intracellular
  proteases and further activation of membrane
  fusion mechanism within endosomes (Simmons et
  al., 2005).
• Then, the endosome opens to release virus to the
  cytoplasm, and uncoating of viral nucleocapsid
  (N) is started via proteasomes which typically
  can hydrolyse endogenous proteins, but they are
  also capable of degrading exogenous proteins such
  as the SARS nucleocapsid protein (Q. Wang et al.,
  2010).
• A different two-step mechanism has been suggested
  (Li, 2016) and in this case the virion binds to a
  receptor on the target host cell surface through
  its S1 subunit and the Spike is cleaved by host
  proteases (Hasan et al., 2020) and then it is
  expected the fusion at low pH between viral and
  host target membranes via S2 subunit.
• Finally, the viral genetic material a single
  stranded RNA is fully released into the
  cytoplasm.

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8.2 Replication-Transcription Complex (RTC)
Formation

• Immediately after release of viral nucleocapsid,
  ssRNA serves as functional mRNA with respect to
  ORF1a and ORF1b encoding polyprotein pp1a
  (440500 kDa) and pp1ab (740810 kDa),
  respectively.
• pp1a is 1.22.2 folds more expressed compared to
  pp1ab dueto differential efficiency of frameshift
  between ORF1a and ORF1b genes.
• These two polyproteins undergo autoproteolytic
  processing yielding 16 nsps, which together form
  the RTC for viral RNA synthesis.
• This functional RTC results into formation of a
  nested set of sgRNAs via discontinuous
  transcription.

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8.3 Synthesis of Viral RNA

• The formation of RTC sets molecular process in
  motion leading to synthesis of multiple copies
  of viral RNA.
• These -ssRNA (negative ssRNA) serves as
  intermediate template.
• Meanwhile, polymerase switches template at short
  motifs, transcription regulated sequences (TRS)
  during -ssRNA synthesis, thereby producing a
  multiple 50-nested set of negative sense sgRNAs
  which, in turn, used as templates to form a
  30-nested set of positive sense sgRNAs.
• Thereafter, they associate with host ribosome,
  synthesizing various structural and accessory
  proteins building multiple virus structure .

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8.4 Molecular Assembly and Release of
SARS-CoV-2

• Most of the structural and accessory proteins
  associated with membrane such as S, M, and E are
  synthesized by endoplasmic reticulum-bound
  ribosomes, whereas other viral proteins,
  including N protein, are translated by free
  cytosolic ribosomes of host cells.
• In addition, these structural proteins also
  undergo posttranslational modification that
  modulate their functions.
• The assembly of virion converges at site of
  endoplasmic reticulumGolgi intermediate
  compartment (ERGIC), wherein M protein provides
  scaffold and orchestrate virion morphogenesis by
  heterotypic interaction with other structural
  proteins, such as M-S and M-E, thereby
  facilitating molecular incorporation.
• Furthermore, M-N interactions mediates
  condensation of the nucleocapsid with the
  envelope along with E protein.
• Post molecular assembly, progeny virions are
  transported in smoothwall vesicle and using
  secretory pathway they are trafficked to plasma
  membrane and eventually exit though exocytosis
  and spread to other parts of body

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9.0 Transmission

• Covid-19 is a contagious viral infection that can
  be spread through inhalation or ingestion of
  viral respiratory droplets as a result of
• ? Coughing ?Sneezing
• ?Talking/singing ?Sharing airspace 30
  minutes infects
• ? Touching infected surfaces are primary sources
  of infection.
• Silent spreaders of Covid-19
• Asymptomatic patients carry active virus in
  their body but never develop any symptoms.
• Pauci-symptomatic (Mild) patients Feel a little
  unwell from covid-19 infection but continue to
  come into close contact with others.
• Pre-symptomatic patients Infected and are
  incubating the virus but no symptoms.
• Children are not immune from this infection and
  their symptoms dont correlate with exposure and
  infection.

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10.0 PATHOPHYSIOLOGY

• 10.1 Asymptomatic Phase
• The inhaled virus SARS-CoV-2 binds to epithelial
  cells in the nasal cavity via angiotensin
  converting enzyme 2 (ACE2).
• In vitro data with SARS-CoV indicate that the
  ciliated cells are primary cells infected in the
  conducting airways.
• The virus undergoes local replication and
  propagation, along with the infection of ciliated
  cells in the conducting airways.
• This stage lasts a couple of days and the innate
  immune response generated during this phase is a
  limited one.
• In spite of having a low viral load at this
  time, the individuals are highly infectious and
  the virus can be detected via nasal swab testing.

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• 10.2 Invasion and Infection of the Upper
  Respiratory Tract
• The virus propagates and migrates from the nasal
  epithelium to the upper respiratory tract via the
  conducting airways and a more robust innate
  immune response is triggered.
• Nasal swabs or sputum should yield the virus
  (SARS-CoV-2) as well as early markers of the
  innate immune response.
• Due to the involvement of the upper airways, the
  disease manifests with symptoms of fever, malaise
  and dry cough.
• There is a greater immune response during this
  phase involving the release of C-X-C motif
  chemokine ligand 10 (CXCL-10) and interferons
  (IFN-ß and IFN-?) from the virus-infected cells.
• The majority of patients do not progress beyond
  this phase as the mounted immune response is
  sufficient to contain the spread of infection.
  For about 80 of the infected patients, the
  disease will be mild and mostly restricted to the
  upper and conducting airways. These individuals
  may be monitored at home with conservative
  symptomatic therapy.

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• 10.3 Involvement Of The Lower Respiratory Tract
  And Progression To Acute Respiratory Distress
  Syndrome (ARDS)
• - Hypoxia, ground glass infiltrates/opacity and
  progression to ARDS
• About 20 of all infected patients progress to
  this stage of disease and develop severe
  symptoms.
• The virus invades and enters the type 2 alveolar
  epithelial cells via the host receptor ACE-2 and
  starts to undergo replication to produce more
  viral Nucleocapsids.
• The virus-laden pneumocytes now release many
  different cytokines and inflammatory markers such
  as interleukins (IL-1, IL-6, IL-8, IL-120 and
  IL-12), tumour necrosis factor-a(TNF-a), IFN-?
  and IFN-ß, CXCL-10, monocyte chemoattractant
  protein-1 (MCP-1) and macrophage inflammatory
  protein-1a (MIP-1a).
• This cytokine storm acts as a chemoattractant
  for neutrophils, CD4 helper T cells and CD8
  cytotoxic T cells, which then begin to get
  sequestered in the lung tissue. These cells are
  responsible for fighting off the virus, but in
  doing so are responsible for the subsequent
  inflammation and lung injury.
• The host cell undergoes apoptosis with the
  release of new viral particles, which then infect
  the adjacent type 2 alveolar epithelial cells in
  the same manner.
• Due to the persistent injury caused by the
  sequestered inflammatory cells and viral
  replication leading to loss of both type 1 and
  type 2 pneumocytes, there is diffuse alveolar
  damage eventually culminating in an acute
  respiratory distress syndrome

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11.0 Symptoms of COVID-19

• COVID-19 affects different people in different
  ways. Most infected people will develop mild to
  moderate illness and recover without
  hospitalization.
• Most common symptoms
• ?Fever ?cough
  ?Tiredness ?loss of taste or smell.
• Less common symptoms
• ?sore throat ?headache ?aches
  and pains ?diarrhoea
• ?a rash on skin, or discolouration of fingers or
  toes ? red or irritated eyes.
• Serious symptoms
• ?difficulty breathing or shortness of breath
• ?loss of speech or mobility, or confusion
  ? chest pain.
• On average it takes 56 days from when someone is
  infected with the virus for symptoms to show,
  however it can take up to 14 days.

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11.1 Covid-19 complications

• ?Acute respiratory failure (ARF) ?Acute
  respiratory distress syndrome (ARDS)
• ?Acute liver injury
  ?Septic shock
• ?Acute kidney injury
  ? Rhabdomyolysis
• ?Acute cardiac injury
  ? Acute brain injury
• ?Pneumonia pulmonary embolism followed by
  extra-pulmonary systemic hyperinflammation
  syndrome.
• ?Adipose tissue increased fat composition
  sustained fat loss in recovered patients,
  elevated plasma F.As and TAGs (hyperlipidemia).
• A?cute Pancreas injury contribute to
  long-lasting diabetes. Insulin resistance,
  hyperglycemia, altered glucose metabolism
  development of T2D.
• ?Disseminated intravascular coagulation/blood
  clots hypertension.
• ?Secondary infections Strep and Staph that
  raises the risk of death.
• ?Multisystem inflammatory syndrome in children
  (MIS-C)

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12.0 COVID-19 Diagnosis

• Clinical features e.g fever, fatigue, Dry cough,
  breathlessness etc
• Screening Laboratory Tests hematologic,
  biochemical inflammatory biomarkers etc.
• Imaging chest x-ray, CT scan
• Molecular Examination RT-PCR, Quantitative
  RT-PCR etc.
• Immunological Assays ELISA, CLIA, IFA etc.
• Novel Techniques- Next generation sequencing,
  CRISPR, LAMP etc.

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13.0 Treatment

• To date, no single medication has been reported
  or proposed to combat the infective viral load of
  SARS-CoV-2.
• However, previous strategies for developing
  proper medications to pulverize SARS-CoV can be
  extrapolated to COVID-19 infection effectively.
• Scientists, several research groups, and
  clinicians across the globe are working towards
  finding effective medications that can curtail or
  eliminate the viral load of SARS-CoV-2.
• Below is a list of natural products/isolated
  compounds or their derivatives and drugs that
  inhibit the coronavirus family

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Categories Compound Name Proposed Mode of Actions Involved Viruses
Antiviral drugs Remdesivir ( GS-5734, Nucleoside analogue of Remdesivir triphosphate) ( RDV-TP ) Inhibitor of RdRp SARS-CoV-2
Antiviral drugs Lopinavir/Ritonavir HIV protease inhibitor HIV infection, SARS-CoV-1, and MERS-CoV
Antiviral drugs Darunavir/Cobicistat Protease inhibitor SARS-CoV-2
Antiviral drugs Favipiravir (T-705) Purine nucleotide RNA polymerase inhibitor RNA viruses and SARS-CoV-2
Antiviral drugs Ribavirin (Guanine analogue) Inhibits viral RdRp SARS-CoV-1 and SARS-CoV-2
Antiviral drugs Umifenovir (Arbidol) Targeting the S protein/ACE2 and inhibits the membrane fusion of the envelope of the virus Influenza and SARS-CoV-2
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Antimalarial drugs Chloroquine ( Synthetic version of quinine and is found in the bark of cinchona trees) Reduces the rate of replication Malaria, systemic inflammatory diseases, and SARS-CoV-2
Antimalarial drugs Hydroxychloroquine Inhibition of glycosylation of host receptors, proteolytic processing, and acidification of endosomes SARS-CoV-2 and autoimmune diseases
Antiparasitic drugs Ivermectin Inhibits nuclear transport Parasitic Infections and SARS-CoV-2
Antiparasitic drugs Nitazoxanide (Anti-helminthic drug) Unclear MERS and SARS-CoV-2
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Adjunctive drugs Corticosteroids/quinolone (n combination) Prevents ARDS SARS-CoV and SARS-CoV-2
Adjunctive drugs Monoclonal Antibodies (Tocilizumab, Sarilumab, Eculizumab, Fingolimod, Bevacizumab) Immunomodulatory effect, inhibition of terminal complement, and antiVEGF medication SARS-CoV-2 and Chronic Inflammatory disorders
Adjunctive drugs ACE-Inhibitors and ARBs ( enzyme ) Activates RAAS mechanism SARS-CoV-2
Adjunctive drugs Interferon-(a and ß) Unclear MERS-CoV and SARS-CoV-2
Adjunctive drugs Vitamin-D (Adjunct with vitamin C and zinc) Inhibits inflammatory response and attenuates cytokine storm SARS-CoV-2
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14.0 Vaccines

• There are four categories of vaccines in clinical
  trials
• Whole Virus Vaccines- use a weakened
  (attenuated) or deactivated form of the pathogen
  that causes a disease to trigger protective
  immunity to it.
• Nucleic Acid Vaccines- use genetic material (DNA
  or RNA) from a disease-causing virus or bacterium
  (a pathogen) to stimulate an immune response
  against it
• Viral Vector Vaccines- use a modified virus (the
  vector) to deliver genetic code for antigen into
  human cells, thus infecting cells and
  instructing them to make large amounts of
  antigen, which then trigger an immune response.
• Protein Subunit Vaccines- use fragments of
  protein from the disease-causing virus to trigger
  protective immunity against it.
• Below is a list of authorized/approved vaccines
  against SARS-CoV-2 for COVID-19 ( FDA Approved,
  Emergency Use Authorization (EUA) vaccines)

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S/No Vaccine Name Vaccine Type Developers Country of Origin Current Schedule and Route of Administration Reported Effectiveness Following Clinical Trial
1. Comirnaty (formerly BNT162b2) mRNA-based vaccine(encodes mutated form of S protein) Pfizer, BioNTech Fosun Pharma Multinational Two doses, 21 days apart, intramuscular injection 95 efficacy in Phase 3 clinical trial (NCT04368728). 92 efficacy in vaccinated healthcare workers .
2 Moderna COVID-19 Vaccine ( mRNA -1273) mRNA-based vaccine Moderna, BARDA, NIAID USA Two doses, 28 days apart, intramuscular injection 94.1 efficacy in Phase 3 clinical trial (NCT04470427) .
3 COVID-19 Vaccine Janssen (JNJ-78436735 Ad26. COV2.S) Non-replicating viral vector Janssen vaccines (Johnsons Johnsons) The Netherlands, US Single dose vaccine, intramuscular injection 85 efficacy in Phase 3 ENSEMBLE trial (NCT04505722).
48
4 COVID-19 Vaccine AstraZeneca (Covishield) Adenovirus vaccine BARDA, OWS UK Two doses, between 412 weeks apart, intramuscular injection 79 efficacy in Phase 3 clinical trial (NCT04516746). 100 efficacy in severe disease and hospitalization patients.
5 Sputnik V (Gam-COVIDVac) Recombinant adenovirus vaccine ( rAd 26 and rAd5) Gamaleya Research Institute, Acellena Contract Drug Research and development Russia Two doses, 21 days apart, intramuscular injection 94.1 efficacy in Phase 3 clinical trial (NCT04530396)
6 CoronaVac (formerly PiCoVacc) Inactivated vaccine ( formalin with alum adjuvant) Sinovac China Two doses, between 1418 days apart, intramuscular 50 efficacy in Phase 3 clinical trial (NCT04456595) .
49
7 BBIBP-CorV Inactivated SARS-CoV-2 vaccine (Vero cell) Beijing Institute of Biological Products China National Pharmaceutical Group (Sinopharm) China Two doses, intramuscular injection 86 efficiency Phase 3 clinical trial ( ChiCTR 2000034780). High effectiveness in terms of neutralizing antibody production in rhesus macaques.
8 EpiVacCorona Peptide vaccine Federal Budgetary Research Institution State Research Center of Virology and Biotechnology Russia Two doses, 2128 days apart, intramuscular injection Phase1/2 trial (NCT04527575) Trial is still going and evaluation regarding efficiency being carried out.
9 Convidicea (Ad5-nCoV) Recombinant vaccine (adenovirus type 5 vector) CanSino Biologics China Single dose vaccine, but also evaluated in trial with 2- doses, intramuscular 65.7 efficiency in Phase 3 clinical trial (NCT04526990).
50
10 Covaxin Inactivated vaccine Bharat Biotech in collaboration with National Institute of Virology), ICMR. India Two doses, intradermally 81 in Interim phase 3 trial
11 Name is yet to be specified Inactivated vaccine Sinopharm and the Wuhan Institute of Virology under the Chinese Academy of Sciences China Final number of doses and interval not yet decided Phase1/2 clinical trial (ChiCTR2000031809) is completed and 72.51 efficacy in on-going phase 3 clinical trial.
12 CoviVac Inactivated vaccine Chumakov Federal Scientific Center for Research and Development of immune and Biological Products Russia Not yet finally decided Phase1/2 trial is undergoing
13 ZF2001 Recombinant vaccine (CHO) Anhui Zhifei Longcom Biopharma ceutical, Institute of Microbiology of the Chinese Academy of Sciences China, Uzbekistan Not yet finally decided, intramuscular injection Phase 3 clinical trial (NCT04646590) is being evaluated.
51
15.0 Control/Prevention

• To prevent infection and to slow transmission of
  COVID-19, do the following
• Get vaccinated when a vaccine is available to
  you.
• Stay at least 1 metre apart from others, even if
  they dont appear to be sick.
• Wear a properly fitted mask when physical
  distancing is not possible or when in poorly
  ventilated settings.
• Choose open, well-ventilated spaces over closed
  ones. Open a window if indoors.
• Wash your hands regularly with soap and water or
  clean them with alcohol-based hand rub.
• Cover your mouth and nose when coughing or
  sneezing.
• If you feel unwell, stay home and self-isolate
  until you recover.

52
16.0 Comparison of SARS-CoV2, SARS-CoV , and
MERS-Co
53
(No Transcript)
54
17. References

1. https//www.who.int/emergencies/diseases/novel-cor
   onavirus-2019
2. https//www.afro.who.int/health-topics/coronavirus
   -covid-19
3. https//en.wikipedia.org/w/index.php?titleSevere_
   acute_respiratory_syndrome_coronavirus_2oldid104
   5920399
4. https//doi.org/10.1016/j.cell.2020.04.013
5. . Romano M, Ruggiero A, Squeglia F, Maga G,
   Berisio R. A Structural View of SARS-CoV-2 RNA
   Replication Machinery RNA Synthesis,
   Proofreading and Final Capping. Cells.
   202091267.
6. S. Raskin, Genetics of COVID-19, Jornal de
   Pediatria, https//doi.org/10.1016/j.jped.2020.09.
   002
7. Nanotechnology for Environmental Engineering
   (2021) 619. https//doi.org/10.1007/s41204-021-00
   109-0

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1. Yadav, R. Chaudhary, J.K. Jain, N. Chaudhary,
   P.K. Khanra, S. Dhamija, P. Sharma, A. Kumar,
   A. Handu, S. Role of Structural and
   Non-Structural Proteins and Therapeutic Targets
   of SARS-CoV-2 for COVID-19. Cells 2021, 10, 821.
   https//doi.org/10.3390/cells 10040821
2. https//doi.org/10.1371/journal.ppat.1008536.g003
3. Jha, N.K. Jeyaraman, M. Rachamalla, M. Ojha,
   S. Dua, K. Chellappan, D.K. Muthu, S. Sharma,
   A. Jha, S.K. Jain, R. et al. Current
   Understanding of Novel Coronavirus Molecular
   Pathogenesis, Diagnosis, and Treatment
   Approaches. Immuno 2021, 1, 3066.
   https//doi.org/ 10.3390/immuno1010004
4. https//en.wikipedia.org/w/index.php?titleSpecial
   CiteThisPagepageInfluenza_pandemicid104212477
   9wpFormIdentifiertitleform
5. https//upload.wikimedia.org/wikipedia/commons/thu
   mb/b/b4/Symptoms_of_coronavirus_disease_2019_3.0.s
   vg/800px-Symptoms_of_coronavirus_disease_2019_3.0.
   svg.png
6. J Gene Med. 202123e3303. https//doi.org/10.1002
   /jgm.3303
7. Audio https//youtu.be/Q2MmREArTds

56
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