Transcript Avian Flu

The Avian flu
The Next Pandemic
• 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
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.
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).
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
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
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.
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.
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.
• 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.
Rate of mutations
• The flu strains
accumulated
nucleotide
substitutions in their
hemagglutinin genes
at a steady rate.
Phylogenetic analysis
• Most of the flu samples
represent extinct side
branches on the
evolutionary tree.
• The flu strains of the
1980’s turned out to be
descended from a single
strain of the 1960’s.
What allowed the surviving lineage
to endure while the other lineages
perished?
*Mutation
Surviving lineages Extinct lineages
sites
Antigenic sites
33
31
Nonantigenic
10
35
sites
*Only mutations that resulted in change of amino acid were counted.
P = .002
Hemagglutin, an Important
Antigenic site
• More than three
quarters of the
changed amino acids
in the “survinving
lineages” occurred at
antigenic sites on
hemagglutinin.
Comparing Influenza’s 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.
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
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.
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.
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.
The Origin of Pandemic Flu Strains
The Red Queen
• Influenza A’s 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 don’t 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.
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 RNP’s between different
strains. This produce new hybrids.
• These new hybrids have never been seen by the
human population. A pandemic will ensue.
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.
Phylogenies cont.
• Compare:
– The Human Northern Territory /60-1968
(H3N2) and
– Human / Victoria / 1968 (H2N2)
• NA’s are closely related but HA’s are
distant.
Phylogenic evidence
• H3 was never seen in
the human population
until 1968.
• Global pandemic
• Reassortment with
pig.
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.
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.
N1H5
1. Travel will be restricted.
Food supply will shut down. People won’t 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
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 weren’t effected that could help.
But in a pandemic no one will be there to
help, everyone will be asking for help.
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.
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?