???? SARS ??????????????

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???? SARS ??????????????

• ???? ?????
• ????? ???? ????? ???? ????

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?????

• ?????
• SARS (Severe acute respiratory syndrome)
• ?????? ???? ????? ?? ???????
• ???? ??? ????? ??? ????? ?????? ??????
• ??????? 2002 ?????? ???????? ??????? ?? ????
  ?????? ????? ????????? ?????? ???

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The SARS Scare

• A cautionary tale of emerging disease caught in
  the act
• http//www.harvardmagazine.com/2007/03/the-sars-sc
  are.html

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Do you remember?

• In a matter of months in early 2003, severe acute
  respiratory syndrome spread to 29 countries,
  killing nearly 10 percent of the people it
  infected.
• No drug could stop SARS, and the disease
  propagated wildly through the ranks of healthcare
  workers.
• One patient, a super-spreader, infected 143
  people, including every one of the 50 doctors and
  nurses who treated him.
• Eerie scenes of Chinese cities being disinfected
  by spray trucks

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?????? ???????
Chinese doctors and nurses wear protective gear
as they tend to a SARS patient in a Beijing
hospital.
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?????? ???????
This diagram detailing SARS transmission in
Singapore shows the important role of
super-spreaders in transmitting the disease.
Five people caused more than half of the 205
cases there.
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It was so many years ago why should we remember
it?

• SARS was declared eradicated by the World Health
  Organization (WHO) in 2005.
• ?? ??? ????? ????? ?????? ??? ??? ???? ?????

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• Ironically, in this age of high-tech medicine,
  the virus was eventually brought under control by
  public-health measures typically associated with
  the nineteenth centuryisolation of SARS patients
  themselves and quarantine of all their known and
  suspected contactsrather than a vaccine.
• But it was tools of the modern era, including
  high-speed communications and sophisticated
  computer modeling, that allowed epidemiologists
  at Harvard and in the United Kingdom to initially
  determine that such an approach could work at
  all.
• The threat, of course, is that our luck might not
  hold next time. That makes it vital to learn from
  the scientific, public-health, and political
  responses to what did happen.
• SARS is the story of a global network of medical
  workers, epidemiologists, virologists, and other
  scientists who responded to a sudden threat with
  record speed, aided by new technologies that
  allowed them to identify the virus, decipher its
  genetic code, and publish it on the Internet.

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?? ?????

• Whether or not SARS returns to afflict humans,
  the disease has taught us much about our lack of
  readiness for the next emergent infection raised
  many questions about the conditions that lead to
  surprisingly frequent outbreaks such as SARS,
  Ebola, bird flu, and Nipah virus and suggested
  how public-health and molecular medicine best
  work together in the prevention and control of
  new diseases.

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????????? ?? ?????

• ????? 2003 ????? ????? ?????? ?? ???? ?????
  ????-????? ???????.
• ?????? ???????? ????? ?? ????? ??????? ?? ????
  ??????.
• ???? ??????? ?????? ?? ???? ????? ????? ????????
  ????? ????? ???? ???? ???.
• ????? ????? ????? ???????? ????? ????? ????
  ?????? ?????.

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????????? ????? ?? ????

• ??? ?-16 ??????? 2002 ?-11 ??????? 2003 (????
  ??????), ????? ?????? ?????? ????? ????? ???????
  ?? ????? ????? Guangdong ?????? ???.
• ???? ???? ?????? 2003 ???? ????? ??????? ??? ??'
  911 ???? ????? Metropole ??????-???? ???? ????
  ????? Guangzhou ?????? ??, ??????? ????? ????
  ???? ????? ?????, ????? ?'??-?? ?? ?????? ?????
  ??????? ??????-????.

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????? ?????

• ?-22 ??????? ??? ????? ???? ????? ?????-????
  ??-4 ????? 2003 ??? ?? ????? ?????, ????? ???
  ???? ??????? ?????? ??????? ????? ????.
• ?"?????" ?????? ????? ????? ???? ??? 2003 ?????
  ???? ????-????, ??????? ????? ????, ??????? ?????
  - ????? ??????? ??????, ????????, ??????
  (???????), ????????? (????).
• ?- 12 ???? ????? ????? ??????? ????????? ??
  ????? ????? ????? ?????.
• ????? ?????? ??????? ????? (?? ?? ??? ?????
  ?????), ???? ?????? ????? "?????", ??? ???? ??
  ???? ????? ??? ?????? ?? ???? ???????.

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????? ?????

• ?????-???? ???? ????? ?????? ??????? ???????
  ??????? ???? ??? ?????. ???? ????? ???? ??????
  ???? ????? ??? ????? ?????, ???? ????? ?????
  ?????? ?????? ????. ????? ?????? ??? ????? - ????
  ?-300 ????? ?????? ????? ??????? ???.
• ????? ?????????? ????? ?????? ??????? ????? ?????
  ????? ????? ????? - ???, ????-????, ????, ??????,
  ??????, ???????, ????? ?????, ????????? ????.
  ???? ????? ??? ????? ???? ?????. ???? ??? ??????
  ??????? ?????? ??????????. ?????? ????? ????
  ????? ?????? ??? ????? ???? ????? ?? ???? ?????
  ?????. ?? ???? ????? 2003 ??? ????? 4836 ????
  ???? 293 ??? ???.

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??? ?????????

• ??? 1.11.02 ??? 26.4.03 ??? ?- SARS ?- 4836
  ?????, ?- 5 ????? / ?- 28 ????? (???? ???? /
  ????-????), ???? ????? 293 (?-6). ???? ???????
  ?? ????? ????? ??????? (?????-???? ????
  ????????).

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Dr. Carlo Urbani

• ????? ??? ?? ?"? Carlo Urbani- ????? ????? ??????
  ???????? ???? ?????????, ??? ????, ?? ??????
  ????? ???????? ??? ???? ????.

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• Italian Dr. Carlo Urbani, 46, an infectious
  disease expert with the World Health
  Organization's Hanoi office, is seen in this
  undated photo.
• On March 29, Urbani died of Severe Acute
  Respiratory Syndrome at age 46, but not before
  leaving his mark.
• The speed with which he recognized the potential
  scope of the illness is credited with containing
  Vietnam's initial outbreak and his death on the
  front lines has prompted some scientists to call
  for the SARS virus to bear his name.

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????? ???? ?????

• 15/3/2003 ????? ??????? ?????? ????? ?? ??
  ??????? ??? ????? ????? ?????? ????? . 
• 17/3/2003 ????? ??????? ?????? ???? ??? ???????
  ?-11 ?????? ???? ????? ????? ?? ????? ?????.
• ????? ??????? ?????? ???? ?????? ????? ?????? ??
  ????? ???????.
• 16/4/2003 ????? ???? ?????? ??????? ??????
  ?????? ????? ?????? ????? ????? 13 ?????? ???
  ?????? ?????.

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SARS CoV

• July 10, 2003
• SARS is a life-threatening form of pneumonia.
• In the course of a few months, an epidemic
  emerged that spread from its likely origin in
  Guangdong Province, Southern China, to 32
  countries. It is caused by a new coronavirus,
  termed SARS CoV.
• Coronaviruses have pretty big RNA genome and
  their life cycle inside host cells differs in
  several ways from other RNA viruses.
• By the end of June 2003, the World Health
  Organization (WHO) had recorded about 8,400 cases
  and 800 deaths. The rapid spread of the disease
  and the high number of deaths makes SARS a global
  threat for which no effective treatment is
  available.

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????? ???? ?????

• Coronavirus
• ???? ????? ??? ??? ?????? ?-Coronavirus . ?????
  ?????? ??? ?? ??? ???????-????? ?????.
• ?????? ??? ??? ?????? ????? ???.
• ??? ??? ??? ??? ???? ????? ???? ???? ?? ?????.
• ????? ?? ???? ?? ??????????? ???? SARS

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Coronavirus from SARS

• Coronavirus from SARS isolated in FRhK-4 cells.
• Thin section electron micrograph and negative
  stained virus particles

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Coronavirus
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Coronaviruses

• Coronaviruses get their name from their striking
  corona (crown) of spikes. These are made of S
  glycoprotein drawn here in blue. These spikes
  (peplomers) bind to host cells and allow the
  virus to enter the cell.
• The virus is enveloped. This means it is cloaked
  in a membrane derived from the host cell. In the
  case of coronaviruses, this membrane is derived
  from inside the cell, not from the cell surface.
• M proteins insert into the membrane, where they
  interact with the spikes. M proteins all seem to
  insert in the envelope but many also connect to
  the nucleocapsid.
• Below the envelope is a gap. Deeper still lies
  the core. This seems to be composed of M protein
  on the outside and contains the RNP
  (ribonucleoprotein). The RNP is a complex of RNA
  (which carries the viruses genetic material) and
  N protein.

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Coronavirus

• Coronaviruses reproduce in the cytoplasm of
  cells.
• They release their genetic material (RNA) into
  the cytoplasm where it directs the production of
  new virus genetic material and virus protein.
• These components collect together to form new
  virus particles.
• The viruses collect in membrane bound sacs and
  are eventually released onto the surface of the
  cell in large numbers.

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Coronaviridae

• ????? ??????? ?? ??????? ????? ??????? ?????????
  ???? 1937.
• ?? ???? ????? 15 ???? ?????? ?????? ????. ??
  ??????? ?? ?? ??? ??? ??? ?? ???, ???????, ?????,
  ??????, ????? ???????.

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????? ???? ?????

• ???? ??????? ????? ????? ????? ???? ?????? ??
  ????? ???? 2003, ???? ?????? ?????.
• ????? ??? ?????? ???? ???? ????? ?????? ?????.
  ??? ??????? ??? ????? ???? ?? ???? ????? ??????
  ????? ????? ?????? ?????? ????? ??????? ????
  ????? ?? ?????? ???? ??.
• ??????? ?????? ????? ?? ???? ???? ?? ??????? ???
  29,736 ???????????.

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?????

• ??? ???????????? ?????? ??? ??????? ??????
  ??????, ?? ?? ???? ??? ??????? ??????? ?????
  ????? ??.
• ????? ??????? ?? ???? ???? ?? ?????.
• ????? ??? ??? 60 ?-220 ?????? (??????? ??? 9-
  10?' ????? ??? ??????? ???? ???? ????????!!!)

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Corona

• ?? ?????? ???????? ?? ??????? ?????? ??????
  ???????? ?????? ???? (peplomer).
• ?????? ??? ?????? ???? ?? ???? ?? ???? ????? ????
  ??? ?????? ?? ????? ?????? ?? (?????? ???????
  ?????? ???).???? ?? ?????? ???, ???? ?????
  ??????? ?????? ????? ??? ???? ????? ??????
  ??????, ?????? ?????? ????? ?? ?????? (????????)
  ??????? ?? ???? ?????.

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??? ?????

• ??????? ??? ?????? ?? ??????? ?????? ?? ???
  ?????? ?????? ?? ???? ?????.
• ???? ??????? ??? ?????? ???????? ??????? ??? ???
  ????? ???????.
• ???? ??????? ??? ???? ????? ?RNA.
• ???? ???? ??? ????? RNA ??? ???? ?-HIV ?????
  ????? ??????.

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Unprecedented collaboration

• 16 April 2003
• GENEVA -- Today, the World Health Organization
  announced that a new pathogen, a member of the
  coronavirus family never before seen in humans,
  is the cause of Severe Acute Respiratory Syndrome
  (SARS).
• The speed at which this virus was identified is
  the result of the close international
  collaboration of 13 laboratories from 10
  countries.

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Unprecedented collaboration

• 16 April 2003
• While many lines of evidence have found strong
  associations between this virus and the disease
  over the last weeks, final confirmation came
  today.

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Prof. Dongwan Yoo has been studying how the SARS
coronavirus infects cells

• SARS attacks the respiratory system, so many
  researchers were surprised to find it was a
  coronavirus. Coronaviruses usually invade cells
  in the digestive system and generally dont
  spread very fast because theyre finicky about
  growing conditions. So far, Yoo has found
  similarities between SARS and two other
  coronaviruses important to agriculture that hes
  been working on bovine coronavirus and the
  porcine reproductive and respiratory syndrome
  (PRRS) virus.
• They share many similar proteins and reproduce in
  the same way, he says.

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39
????? ????? ??????

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  ????? ?????.
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  ??????? ??? ????? ??????? ????? ??? ?????? ?????
  ?????? ????? ??? ?????? ????? ???? ???? ?????
  ??????.

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  ?????.
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• ????? ??????? ??????? ?? ??? ????????? (???????
  ???????? ??????) ?? ?????? ????? ?????? (???? -
  ??? ?? ???????), ?? ?? ??? ???.

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?????? ??????

• ??? ?????? ?? ??????? ???? ???? ????? ???? ?????
  (???? ?????? ?? ????? ???????? ?? ?????? ??????).
  
• ????? ?? ????? ??????? ?????? ?????? ?????-
  ??????? ??????? ????? ???? ?????? ?? ????? ?????
  ???????.
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  ??????? ??? ?? ?????? ????? ??????.
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  ??????? ???? ???? ????? ?????? ?????.
• ???? ?? ???? ???????? ???? ??????? ???? ?????
  ??????? ??? ?? ?????.

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??? ????? ?? ?????
43
????? ????

• ????? ????? ??? ???? (SARS) ????????? ???????
  ??????? ?????.
• ????? ??????? ??????, ????? ??? ?? ????? ????
  ???? ??, ????? ?? 7761 ?????, 623 ??? ?????.
• ????? ????? ??????? ????? ???? ???? ( ???? ?- 38
  ????? ), ???? ????? ????? ???.
• ??? ??????? ?????? ????? ????? ??????? ?????
  ??????? ????? ???????? (??????? ????? ????? ).

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????? ????

• ??? ???? ??? 38 ????? ?????? .
• ???? ?????? .
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• ?????? ???? ???? ?? ???? ????? 10 ???? ??? ?????
  ???????.
• ????? ?? ??????? ?????? ??? ??????? ?? ????
  ????.
• ???? ????? ????? ????? ?? ????????? ????? ???
  ???? ??? , ?????? ,????? ????? ,?????, ????? ,
  ????? ???????? .

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? ? ? ? ? ? ? ? ?

• ?? ????? ????? ????? ????? ?????? ??? ??? ????
  ?????? ???? ???? ?? ????? ??????? ????
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• ??????? ?????? ?????? ????? ????? ????? ???????
  ?? ??? ?????? ????? ?????

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? ? ? ? ? ? ? ? ?

• ?????? ??? ?????? ?????? (???, ?????), ???? ?????
  ??? ?? ?????? ??? ?????? (???? ?"? ??????), ???
  ??????? ????? ????? ?????? ????? ??????? ??
  ?????.
• ??? ?? ???, ???? ????? ??? ???? ?? ???? ???
  ?????? ????? (??? ?????, ???? ????? ????? ??,
  ????? ??????? ?????? ???? ????? ????, ???').
• ????? ?????? ??????, ?????? (?'????) ?? ?????
  ??????? ????? ??? ??? ???, ???? ?? ??? ????, ????
  ??, ?????? ????? ??? ?? ???????

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? ? ? ? ? ? ? ? ?

• ????? ???? ?????? ???? ???? ?????? ??????? ?????
  ????? ?? ??? ??????? ??????, ?? ???? ?????? ???
  ??? ?????.
• ??? ????? ?? ????? ?????? ?"? ???? ???? ?? ?????.
  
• ??? ??? ?? ???? ?? ????? ?? ???? ???? ???????
  ???????, ??? ???? ??? ?? ???? ????? ???? 10 ????
  ??? ????? ??? ???? ?????.

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???? ?????

• Coronaviruses have a very large (for RNA viruses)
  single strand genome, in fact the largest of all
  of the RNA viruses. The genome is positive sense
  (that is, the same sense as the mRNA) and is
  non-segmented (c.f. the orthomyxoviruses). The
  genomic RNA is capped and polyadenylated and
  ranges in size from 27 to 32kB.
• It is the large size of the genome coupled with
  the lack of proof reading in RNA polymerases that
  leads to the high mutation frequency in
  coronaviruses.
• Several coronaviruses have been sequenced,
  including the SARS virus. The order to the genes
  is always the same. At the 5 end is the
  polymerase (pol) and this is followed by four
  structural proteins that are found in all
  coronaviruses.

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• Attachment
• Fusion penetration
• Replication
• Translation
• Assembly
• Exocytosis

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????? ????? ?? ?????

• A coronavirus virion lands on the cell surface
  and binds to cell surface receptors using its
  projecting spikes.
• It then enters the cell by membrane fusion with
  the plasma membrane or by receptor mediated
  endocytosis.

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????? ????? ?? ?????

• The viral genome (which is ss RNA) enters the
  cytoplasm.
• The genomic RNA creates a - version of itself and
  so forms a replication complex attached to
  membrane.

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????? ????? ?? ?????

• These replication complexes then produce new
  genomic RNAs and (subgenomic) mRNAs.
• mRNAs code for new viral proteins, including N, M
  S.
• Rybosomes attach to (subgenomic) mRNAs and
  translate them to the viral proteins.
• The N protein joins the new genomic RNA to form
  new RNPs (ribonucleoproteins).

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????? ????? ?? ?????

• These RNPs attach to the membrane where S (Spike)
  proteins and M proteins have previously
  assembled.
• The RNP buds into the lumen of the vesicle and
  finally the membrane bound RNP and its radiating
  spikes detaches and comes to lie free in the
  lumen as an immature virion.

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????? ????? ?? ?????

• These particles progress up the periphery of the
  Golgi apparatus, maturing as they do so into a
  denser and more icosahedral form.
• The new virus particles collect in large vesicles
  and are finally released onto the cell surface to
  start the cycle again.

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Details of the life cycle of SARS coronavirus

• July 10, 2003A team of scientists studying
  Severe Acute Respiratory Syndrome (SARS) has, for
  the first time, described how the SARS virus
  manufactures several of the materials required
  for making copies of itself.
• "It is essential, when you are looking for ways
  to stop a disease, that you know exactly how
  viruses make copies of themselves and spread,"
  explained Dr John Ziebuhr, from the University of
  Wÿrzburg in Germany.

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Details of the life cycle of SARS coronavirus

• July 10, 2003
• The team has revealed which nucleic acids and
  proteins are produced by SARS coronavirus (SARS
  CoV) for viral replication.
• "This work could lead to the development of
  effective anti-SARS drugs. Now that we know the
  properties of some of the proteins necessary for
  viral replication, we can discover ways to stop
  it, and prevent the virus from spreading", said
  Dr Ziebuhr.

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Details of the life cycle

• Let me briefly run you through the coronavirus
  life cycle.
• As I mentioned before, the virus binds to
  specific receptors on target host cells, and
  binding and fusion results in the deposition of
  the nucleocapsid and ultimately the genome into
  the cytoplasm.
• The first thing that the genome wants to do is be
  translated by host ribosomes. This produces the
  RNA-dependent RNA polymerase complex, which then
  recognizes the three-prime end of the genome, and
  produces a full-length negative-strand copy of
  the genome.
• Also, by multiple steps the polymerase produces a
  series of subgenomic messenger RNAs.

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Details of the life cycle

• These messenger RNAs form a so-called three-prime
  nested set, and each of them consists of a leader
  sequence of 70 to 100 nucleotides fused to some
  internal point on the genome. Each of these has a
  negative strand counterpart as well.
• Each of the resulting subgenomic RNAs then serves
  as a message for translation of one of the
  downstream genes.

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Details of the life cycle

• Another remarkable feature about coronavirus RNA
  synthesis is the very high rate of RNA-RNA
  recombination that occurs in these viruses.
• If two strains or two mutants of a particular
  coronavirus end up infecting the same cell,
  something on the order of 25 percent of the
  progeny will turn out to be recombinants.
• This recombination occurs, unlike DNA
  recombination, not by a breaking and joining
  mechanism, but rather by a so-called template
  switching mechanism or a copy-choice mechanism,
  where the RNA polymerase will be copying one
  template, detach from that template, still
  hanging onto the nascent RNA strand, and then
  reattach to the homologous position of a
  different template and resume synthesis.
• That will result in a molecule that looks like
  this up to this point, and like the other strain
  up to here. That's how recombinants can be
  generated.

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Details of the life cycle

• The nucleocapsid assembles from the nucleocapsid
  protein, and from progeny genomes meet up in the
  cytoplasm, and then bud into the budding
  compartment, resulting in virion formation.
• Viruses are then transported via smooth-walled
  vesicles out of the cell.
• So one virus can go in, a hundred to a thousand
  viruses can leave the cell.

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Video of the effect of SARS on the Hong Kong MTR
(Subway System(
http//www.youtube.com/watch?v2uxuFcLnbgs