The Avian flu

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The Avian flu

• The Next Pandemic

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• At the end of every summer million of ducks and
  wild geese mass on Canadian and Siberian lakes
  for their annual migration.
• Influenza blooms.
• In intestinal tract of juveniles
• Diverse strains
• Shed virus as they migrate south

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Influenza in Mammals

• In humans and pigs influenza is very pathogenic.
• Infects the respiratory tract.
• Spread by aerosol.
• Three genera of Influenza A, B, and C.
• B and C endemic to human population
• Type A is mostly found in birds
• A, is most lethal to humans.

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Evolutionary Shape Shifters

• Compared to other pathogens, influenza A is
  evolving at record breaking speed.
• From year to year its proteins change amino acids
  to create modified strains requiring new vaccines
  (antigenic drift).
• About every 20 -30 years influenza A will change
  drastically enough to jump species (antigenic
  Shift).

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Influenza A

• Hemagglutinin (HA)
• Species specificity
• Main antigenic determinant
• Pandemic result of new HA
• Neuraminidase
• M2 (protein pump)
• Lipid envelope
• Single stranded RNA
• Eight segments called ribonucleoproteins (RNAPs)
• make up 10 genes

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NA removes sialic acid and allows for escape
HA binds to Sialic acid on Intestinal and
respiratory cells
M2 pumps ions into the interior of endosome to
uncoat virus and release RNAPs
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Mutation rate of Influenza

• The synthesis of RNA is radically error prone
• DNA polymerases proof read and auto corrects
  their mistakes.
• 1 mutation every billion nucleotides
• RNA polymerases does not proof or correct their
  copy
• Error rate is 1 million times higher than DNA
  pol.
• Progeny often referred to as a mutant swarm.
• Lives on the edge of error catastrophe.

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Human Immune system

• The aquired or specific immune system is able to
  create lymphocytes that are specific for any
  possible antigen.
• Once an immune response has been launched the
  bodies immunity keeps in memory every antigen
  that it has ever responded to.
• Secondary infections are quickly and vigorously
  attacked.

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Evolution of Influenza

• To persist from year to year a strain must be
  able to infect naïve hosts who have never been
  exposed to its type of HA.
• Fitch and colleagues hypothesized that strains
  Influenza A which developed new antigenic sites
  would have a selective advantage.

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• Fitch looked at flu strain that had infected
  humans from 1968 1987.
• The frozen flu samples constitute a fossil record
  one which genes could be sequenced.

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Rate of mutations

• The flu strains accumulated nucleotide
  substitutions in their hemagglutinin genes at a
  steady rate.

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Phylogenetic analysis

• Most of the flu samples represent extinct side
  branches on the evolutionary tree.
• The flu strains of the 1980s turned out to be
  descended from a single strain of the 1960s.

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• What allowed the surviving lineage to endure
  while the other lineages perished?

Mutation sites Surviving lineages Extinct lineages
Antigenic sites 33 31
Nonantigenic sites 10 35
Only mutations that resulted in change of amino
acid were counted. P .002
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Hemagglutin, an Important Antigenic site

• More than three quarters of the changed amino
  acids in the survinving lineages occurred at
  antigenic sites on hemagglutinin.

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Comparing Influenzas Antigenic Drift to The
Neutral Theory

• To further test the hypothesis that the human
  immune system was driving the evolution of
  Influenza A, Fitch and colleagues compared the
  mutations found in 357 influenza strains isolated
  between 1985 and 1986 to the Neutral theory.
• Neutral theory
• Mutations resulting in amino acid changes are
  deleterious and eliminated by selection.
• Mutations to synonymous codons are neutral and
  may become fixed in the population by genetic
  drift.

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At First Glance

• Of the 331 nucleotide substitutions, 191 (58)
  were silent and 140 (42) were replacement
  substitutions
• This was consistent with the neutral theory

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A Closer look

• When researchers looked at just the hemagglutinin
  gene they identified 18 codons that had
  significantly more replacements substitutions
  than silent substitutions.
• All 18 codons were for amino acids at antigenic
  sites.
• Not consistent with the neutral theory. The
  immune system was pushing the evolution of
  Influenza A.

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Vaccines

• Vaccines take months to prepare. Flu season is
  between October and March.
• The flu virus antigenic make up must be
  predicted well in advance of the flu season in
  order to stock pile enough for an epidemic.

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Predicting the Next Flu.

• Robin Bush and colleagues devised a way to
  predict which circulating flu strains is most
  likely to have surviving descendents in the
  future.
• It will be the current circulating strain with
  the most mutations in the 18 codons known to be
  under positive selection.

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The Origin of Pandemic Flu Strains
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The Red Queen

• Influenza As extraordinary heterogeneity allows
  it to resist the immune system.
• A single amino acid substitution can assure a
  strains survival to the next season.
• Point mutations dont totally outwit the
  immulogical memory of the body.
• The high level of partial immunity remaining in
  the community ensures that antigenic drift will
  not cause a pandemic.

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The Making of a Pandemic

• Influenza can mutate by great leaps.
• RNA is packaged in separate segments. a
  co-infection of a host by two different subtypes
  can result in a reassortment of their genes.
• Influenza can trade RNPs between different
  strains. This produce new hybrids.
• These new hybrids have never been seen by the
  human population. A pandemic will ensue.

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The Evidence is in the Phylogeny

• The influenza stains can be broken up into
  distinct clades based on the immunoprotein.
• The phylogenic tree gives species, year and
  subtype.
• H3N8
• Hemagglutinin 3
• Neuraminidase 8
• Each hemaggluinin group constitutes a clade.

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Phylogenies cont.

• Compare
• The Human Northern Territory /60-1968 (H3N2) and
• Human / Victoria / 1968 (H2N2)
• NAs are closely related but HAs are distant.

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Phylogenic evidence

• H3 was never seen in the human population until
  1968.
• Global pandemic
• Reassortment with pig.

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Phylogenic evidence cont

• Pigs are susceptible to both bird flu and pig
  flu.
• Pig strains sometimes infect humans.
• Flu pandemic begin when humans strains and bird
  strains simultaneously infect a pig and swap
  genes, and later move to humans.

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1918 Flu

• Researchers have Isolated and sequenced the genes
  from the 1918 flu.
• The 1918 flu came from birds.
• It killed more people in 2 months than HIV has
  killed in 20 years.

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N1H5

• Travel will be restricted.
• Food supply will shut down. People wont travel
  between countries.
• Drugs come from other countries. We will run
  short on pharmaceuticals.
• Oil is shipments are likely to lag at
  transportation between countries grinds to a
  halt. Heat in the winter months may be short
  supply

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N1H5

• We have very little surge room in our hospitals.
  
• Patients will be in gymnasiums and coliseums.
• In Katrina we had 48 other states and other
  countries that werent effected that could help.
  But in a pandemic no one will be there to help,
  everyone will be asking for help.

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N1H5

• Mask will run out.
• No one will be allowed to leave their house
  without a mask.
• Church and schools will all close.
• Many businesses will shut down
• Quarantines will be enforced.
• President Bush is talking about Marshal Law.

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N1H5

• How do we handle the dead.
• 1.5 million dead in this country alone.
• We need to start planning for this.
• How many Body bags does our community have?