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SEVERE ACUTE RESPIRATORY SYNDROME _SARS_

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					SEVERE ACUTE RESPIRATORY
SYNDROME (SARS)
Winnie A. Apidi
Student No. 7643853
March 22, 2011
Introduction
 Coronaviruses are    large, enveloped,
  positive sense, single-stranded RNA
  viruses
 Responsible for upper repiratory tract
  infections e.g. common cold
 Coronavirus genus is divided into 3
  groups: SARS stipulated to be in Group II
Severe Acute Respiratory Syndrome
 Feb 2003, cases of atypical pneumonia of
  unknown aetiology in Guangdong, China
 Outbreak spread to Asia, Europe, North
  America
 ~8000 cases and 774 deaths
 Transmission stopped after four months
 Rapid control globally:
 ◦ Easy I’D
 ◦ Isolation of infected
SARS
 2004: 3 cases of lab-based acquired
  infections, and re-introduction from
  animals
 Not sufficient secondary human-human
  transmission to generate outbreak
Epidemiology
 Nosocomial infectcion strikingly   (22-40%
  were healthcare workers)
 Incubation period 2-10 days
 Transmitted through respiratory droplets
 Generated through hospital procedures
 Fecal-oral transmission also possible as
  SARS-CoV can survive in feces for 1-
  2days w’out losing infectivity
Disease
 SARS is   characterized by:
 ◦   Fever
 ◦   Chills
 ◦   Malaise
 ◦   Headache
 ◦   Cough
 ◦   Dyspnea
 ◦   Pneumonia (radiologically)
Immune response
 Pro- andanti-inflammatory cytokines
 detected during SARS-CoV infection
 ◦ Interleukin 13, 16,TNFα and TGFβ
 ◦ IL-18 found to be suppressed
 Serum antibodies detected 20 days after onset
   of infection: IgM then IgG
 Antibodies recognize N protein
Diagnosis of SARS-CoV
   Lab confirmation based on virus isolation,
    detection of viral RNA and serologic assays
   SARS-CoV replicates in Vero-E6 cells and fetal
    rhesus monkey kidney cells
   Viral RNA can be extracted and RT-PCR or
    nucleic acid-based amplification done
   Antibodies can be detected by ELISAs using
    substrates to N protein and Western Blots of
    infected cells
   Biological assays such as microneutralization test
    can be used to measure specific immunoglobulin
    inhibiting growth of SARS-CoV in culture
Animal reservoirs
 Non-SARS cases    lacked SARS-CoV
  antibodies
 Horse-shoe bats
 Palm civet cats
SARS-CoV isolated from animals
Genetically…
 SARS-CoV is
  genetically &
  structurally a typical
  coronavirus
 Genome encodes 4
  structural proteins:
    ◦   nucleocapsid (N)
    ◦   Membrane (M)
    ◦   Envelope (E)
    ◦   Spike (S)
    ◦   S gene has been
        associated with
        disease progression
Spike (S) protein




•S protein induces virus binding, fusion and entry
•Consists of signal peptide and extracellular
domain with 2 subunits S1 & S2
•S1 enhances virus binding to receptor
angiotensin-converting enzyme ACE2 via its RBD
•Forms core with S2 thereby initiating fusion &
entry into cell
SARS-CoV replication
SARS-CoV replication
 Cell entry by attachment of S to ACE2
  receptors
 Triggers fusion of viral & plasma
  membranes
 Entry of nucleocapsid into cytoplasm
 ORFs 1a & 1b of replicase translation
 Viral Proteins synthesized
 Undergo translational proteolytic
  processing into key enzymes
SARS origin & evolution
   Originally reported as a result of zoonotic shift from
    palm civet cat or raccoon dog
   However, origin is still unclear
   Indication of recombination shown phylogenetically
   Recombination useful in eliminating frequent
    deleterious mutations in RNA viruses
   Lack of homology between CoVs indicates that not a
    single recombination event.
   Translational frame shifts occur leading to additional
    ORFs with deletions.
   Not clear whether deletion precede or follow
    transfer of CoV into humans
Phylogeny and recombination
 Phylogenetic studies   show that SARS-CoV
  has a mammalian ancestry
 It is most closely related to Group II
  CoVs
 Intermediary host is still unclear
 Recombination of RNA-dependent RNA
  polymerase with those of CoVs suggests
  that SARS may be old, diverse and
  changeable not yet discovered in its
  natural hosts
Recombination nature of SARS
Antigenic variation
 SARS may     not have emerged due to a
  single recombination event but due to
  genetic drift
 Accumulation of genetic mutations over
  time
 Signature variation residues in S protein
  observed in civet cats
 Overall mutation rate is low-moderate
 Variation causing SARS-CoV to be unique
  still being investigated
Comparison of SARS-CoV and civet
COV
Antigenic variation
 SARS-CoV shown to have evolving
  heterogeneity
 This questions how protective a specific
  vaccine strain could be and possibility of
  imune escape
 Some S glycoprotein variants have been
  found to be resistant to antibody
  neutralization
 Others show enhanced entry in presence of
  certain antibodies
 Others have lower affinity to to ACE2
  domain
Antigenic variation
 Amino acid   substitutions also detected in
  S and M proteins
 Y442C & L472F have been related to
  incorporation of protein to virions and
  this alters antigenic structure
Vaccines
 Vaccines targeting CoVs are in existence
 Various approaches to a SARS-CoV vaccine:
    ◦ Inactivated SARS-CoV-based- easy to generate as
      involve whole killed virus particles
    ◦ S-protein-based vaccines-
      S protein is a type 1 transmembrane glycoprot.
      Induces neutralizing antibodies, virus binding, fusion &
       entry
      Has 2 subunits: S1 & S2. S1 binds to ACE2, angiotensin
       converting enzyme causing RBD in S2 to induce fusion
       between virus and target cells & entry
Vaccines
 S-protein based vaccines   include:
 ◦ Use neutralizing antibodies raised against the
   entire S proteins or its fragments
 ◦ Use strong neutralizing antibodies recognizing
   different epitopes of RBD, thus blocking RBD-
   ACE2 interaction therby blocking attachment
 ◦ Antibodies raised are generated thru
   monoclonal/polyclonal technology or
   vaccination
 ◦ Used to control severe disease
vaccines
Asante!




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