SARS (severe acute respiratory syndrome )

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¢ SARS-CoV genome
¢ S (Spike) protein
¢ Small Envelope Protein E
¢ Nucleocapsid proteins

　

　

u In March 2003, a novel coronavirus (SARS-CoV) was discovered in association

     with cases of severe acute respiratory syndrome (SARS).

　

u There are three groups of coronaviruses; groups 1 and 2 contain mammalian

     viruses, while group3 contains only avian viruses

　

u Human coronaviruses (HCoVs) are found in both  group 1 (HCoV-229E) and group 2 (HCoV-OC43)

     and  are responsible for ~30% of mild upper respiratory tract illnesses.

　

u SARS-CoV is not closely related to any of the previously characterized coronaviruses
　
　

SARS-CoV is not closely related to any of the previously characterized coronaviruses

                       

Coronavirus - Pathogenesis

　

u These viruses infect a variety of mammals & birds. The exact  number of human isolates are

       not known as many cannot be grown in culture. In humans, they cause:

    u Respiratory infections (common), including Severe Acute  Respiratory Syndrome (SARS)
    u Enteric infections (occasional - mostly in infants <12 months)
    u Neurological syndromes (rare)

u  They are transmitted by aerosols of respiratory secretions, by the faecal-oral route, and

        by mechanical transmission

u  greatest incidence in children in winter
　

Coronavirus –Morphology

　

u irregularly-shaped, ~60-220nm in diameter
u outer envelope bearing distinctive,  'club-shaped' peplomers
       (~20nm long x 10nm at wide distal end)
u This 'crown-like' appearance (Latin, corona) gives the family its name.

       

u S - Spike protein :  receptor binding, cell fusion, major antigen
u E - Envelope protein : small, envelope-associated protein
u M - Membrane protein : transmembrane – budding & envelope formation
     
HE - Hemagglutinin-esterase
The genome is associated with a basic phosphoprotein, N.
　

Coronavirus - S, E, M, and N

　

u The structural proteins of coronaviruses (S, E, M, and N) function
      during host cell entry and virion morphogenesis and release.
u During virion assembly, N binds to a defined packaging signal on
      viral RNA, leading to the formation of the helical nucleocapsid
u M is localized at specialized intracellular membrane structures,
      and interactions between the M and E proteins and nucleocapsids
      result in budding through the membrane
u The S protein is incorporated into the viral envelope, again by
      interaction with M, and mature virions are released from
      smooth vesicles
　

Coronavirus -Replication

　

u Entry occurs via endocytosis & membrane fusion  (probably mediated by E2).

u Replication occurs in the cytoplasm
u Assembly occurs by budding into the golgi apparatus, particles being transported to the surface of
      the cell by the secretory nature of this organelle & released.
　

SARS-CoV genome

　

u The genome of SARS-CoV is a 29,727-nucleotide, polyadenylated RNA,

      and 41% of the residues are G or C,  has 11 open reading frames.
u The genomic organization
      (5’-replicase [rep], spike [S], envelope [E], membrane [M],
     nucleocapsid [N]-3’) and a short untranslated regions at both termini.
 
u Phylogenetic analyses and sequence comparisons showed that
     SARS-CoV is not closely related to any of the previously
      characterized coronaviruses
　
Spike Protein

　

u type I membrane glycoproteins :  responsible for both binding to receptors on host cells  and for membrane fusion.
u S proteins also contain important virus-neutralizing epitopes
u  amino acid changes in the S proteins can dramatically affect the virulence and in vitro host cell tropism of the virus 

          

　

SARS-Cov : Spike Protein

u The S (Spike glycoprotein) (21,492-25,259 bp) encodes a
     surface projection glycoprotein precursor predicted to be
     1,255 amino acids in length
u The S protein of SARS-CoV has 23 potential N-linked glycosylation sites.
u amino and carboxyl termini of the S protein that are conserved
u S2 domain is more conserved than the S1 domain 
　

Conserved motifs in coronavirus S proteins : C terminus

　

Small Envelope Protein E (26,117 - 26,347)

　

u The small envelope protein E (26,117 - 26,347) encodes a predicted

      protein of 76 amino acids.
•
u the predicted protein exhibits significant matches to multiple
     envelope (alternatively known as small membrane) proteins from
     several coronaviruses.
u predicted protein is a member of the well-characterized NS3_EnvE protein family. This protein is a component of the viral envelope, and  conserved sequences are also found in other viruses, including gastroenteritis virus and murine hepatitis virus.
　

Membrane Glycoprotein M

　

u Membrane Glycoprotein M (26398-27063) encodes 221  amino acids

u The association of the spike glycoprotein (S) with the matrix localization glycoprotein (M) is an essential step in the formation of the viral envelope and in the accumulation of both proteins at the function site of virus assembly
u three trans-membrane helices, located at approximately residues 15-37, 50-72 and 77-99, with the 121 amino acid hydrophilic domain on the predicted inside of the virus particle, where it is believed to interact with the nucleocapsid.
　

Nucleocapsid proteins

　

u  The protein(422 amino acids) encoded by the Nucleocapsid gene  (28,120-29,388) aligns well with nucleocapsid proteins from other representative coronaviruses

u  a short lysine rich region (KTFPPTEPKKDKKKKTDEAQ)  appears to  be unique to SARS
u  It is possible that the SARS virus nucleocapsid protein has a novel nuclear function
u  the basic nature of this peptide suggests it may assist in RNA binding.

　

      

  SARS Therapy Targets

　

 

　

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