B io Factsheet

www.curriculum-press.co.uk Number 200

The Biology of bird flu

Bird flu isn’t on any of the current Biology specifications, so why
bother with a Factsheet on it? Because it offers Chief Examiners
lovely opportunities to test your understanding of viruses, diseases,
immunity and data analysis. Just because it isn’t on the specs,
doesn’t mean it won’t be in the exam and it makes for fascinating
Biology!
This Factsheet summarises what avian influenza is, how it spreads,
how it infects humans and what we should be doing about it.
There are three types of influenza viruses: A, B, and C. Influenza
type A viruses are divided into subtypes and named on the basis of
two proteins (antigens) on the surface of the virus: hemagglutinin
(HA) and neuraminidase (N). In Fig.1 the hemagglutinin proteins
look like spikes on the surface of the virus and the neuraminidase
proteins look like mushrooms (Fig1.)
Fig 1. H5N1 virus
There are 16 known HA subtypes and 9 known N subtypes. Many
different combinations of HA and N proteins are possible.For
example, an “H7N2 virus” is a type of influenza A that has an HA 7
protein and an N 2 protein. Similarly an “H5N1” virus has an HA 5
protein and an N 1 protein.
Although there are lots of potential combinations of these proteins,
only a few subtypes (i.e., H1N1, H1N2, and H3N2) are currently in
general circulation among people. Other subtypes are found most
commonly in other animal species. For example, H7N7 and H3N8
viruses cause illness in horses, and H3N8 has recently been shown
to cause illness in dogs.
Influenza type A viruses can infect people, birds, pigs, horses, and
other animals, but wild birds are the natural hosts for these viruses.
Question
How would we name an avian flu virus with hemagglutinin
molecule 3 and neuraminidase molecule 2?
Answer : H3N2

N
Influenza viruses - structure

1 1 1 HA (Hemagglutinin)
HA 2

1 1

M2 M1
NS2

1 • abbreviated H or HA
1 • "key" to gaining access
RNPs 2 into the host cell
1 • plays a singnificant role
1
in membrane fusion

2 N (Neuraminidase)
• abbreviated N or NA
• needed for the newly replicated viruses to
Also on the surface of the virus are M2 proteins, which leave the host cell so acts as "scissors"
allow the virus to adjust its interior acidity.

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Fig 2. How the avian virus attacks

1. Attachment
The hemagglutinin (HA) protein spikes bind
1 to the surface of a cell. Specifically, they bind
to three sialic acid molecules on the surface
of the cell membrane
2. Endocytosis
cell membrane The virus is enveloped in
2 a capsule made from the
cell’s membrane and
enters the cell by
endocytosis

protons
HA protein

3
3. Acidfication
Once inside, the proton pump
virus’s M2
protein pumps
hydrogen ions
into the capsule,
to make it more
acidic. The fall in
pH induces a
dramatic change
in shape of the
hemagglutinin
protein.

4. Apposition
4 The hemagglutinin bends
and pulls the virus capsule
towards the endosome
membrane.

5. RNA Release RNA

When the capsule becomes acidic
enough, the virus capsule merges with the 5
endosome. Eventually, a hole is formed.
The viral RNA enters the cytoplasm and
migrates to the cell’s nucleus where the
1
Release
virus copies its RNA Budding Attachment
packaging
Post-translational processing
6. Newly assembled viral particles are released Endocytosis,
Translation Acidification
from the cell, in a process known as budding.
Eventually, the cell dies off. Fusion/ 2 3
uncoating

7. The new viruses then attach themselves Nucleus 5 4

to new cells, starting the process of cytoplasm
replication again.

Humans can be infected with influenza types A, B, and C viruses. Subtypes of influenza A that are currently circulating among people
worldwide include H1N1, H1N2, H3N2 and, best-known of all, H5N1viruses.
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H5N1
Influenza A (H5N1) virus is an influenza A virus subtype that occurs mainly in birds, is highly contagious among birds, and can be deadly
to them. Outbreaks of avian influenza H5N1 occurred among poultry in eight countries in Asia (Cambodia, China, Indonesia, Japan, Laos,
South Korea, Thailand, and Vietnam) during late 2003 and early 2004. More than 100 million birds in the affected countries either died from
the disease or were killed in order to try to control the outbreaks. Since then, the virus has spread to wild birds and poultry in Europe, Africa
and the Near East (Fig 3)

Fig 3.

The H5N1 virus has now

infected humans in Azerbaijan,
Cambodia, China, Djibouti,
Estonia Egypt, Indonesia, Iraq, Lao
People’s Democratic Republic,
Denmark Myanmar, Nigeria, Pakistan,
Russia Thailand, Turkey, and Vietnam.
Lithuania It is a very dangerous disease.
UK
As of 3rd April 2008, of the 378
Germany people confirmed infected by
Poland the World Health Organisation
(WHO), 238 had died. This
makes bird flu especially deadly
France compared to other flu viruses.
Switz. Austria Hungary
A Brief History of
Romania
Italy Influenza Pandemics
Bosnia Black Sea 1918 Flu Pandemic, or the
“Spanish Flu”
Bulgaria 20 – 50 million deaths
Albania Turkey world-wide more than
the casualties from
WWI itself
1957 Asian Flu Pandemic
Greece 2 million deaths
1968 Hong Kong Flu
Pandemic
1 million deaths
Mediterranean Sea 2006 Avian Flu ??
Israel WHO reports 373
confirmed human
cases since 2003,
Egypt with 236 fatalities

What are the risks to humans from the current H5N1 outbreak?
Most human cases have occurred in rural or semi-rural areas where
many households keep small poultry flocks, which often roam freely.
Exposure is considered most likely during slaughter, plucking, and
preparation of poultry for cooking. However, infected birds shed
large quantities of virus in their faeces, These dry, turn to dust and
can be inhaled.
H5N1 virus is found in all tissues throughout an infected bird’s
carcass. In several such instances, it has been reported that the
person who slaughtered or prepared a sick bird for consumption
developed fatal illness, while family members who merely ate the
chicken did not.
Influenza A viruses have infected many different animals, including
ducks, chickens, pigs, whales, horses, and seals.
1998, only H1N1 viruses circulated widely in the U.S. pig population.
However, in 1998, H3N2 viruses from humans were introduced into
the pig population and caused widespread disease among pigs.
H3N8 viruses from horses have now crossed over and caused
outbreaks in dogs.
Avian influenza A viruses may be transmitted from animals to humans
in two main ways:
• Directly from birds or from contaminated environments to people.
• Through an intermediate host, such as a pig.. For example, if a
pig was infected with a human influenza A virus and an avian
influenza A virus at the same time, the new replicating viruses
could mix the genetic information (reassortment) and produce a
new virus that had most of the genes from the human virus, but
a hemagglutinin and/or neuraminidase from the avian virus. The
resulting virus might then have a new and unique set of surface
proteins that increased its ability to infect humans.

Influenza A viruses normally seen in one species can sometimes

cross over and cause illness in another species. For example, until
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Most people would have little or no immune protection against the
new virus. If this new virus causes illness in people and could be
transmitted easily from person to person, an influenza pandemic
could occur.
It is also possible that this genetic reassortment could occur in a
human who becomes infected with avian and human influenza A
viruses.
The new virus could then possess a hemagglutinin against which
humans have little or no immunity. This could then lead to pandemic
influenza i.e. a worldwide outbreak.
In the past, avian flu viruses have not commonly infected humans.
Consequently, there is little or no immune protection against them
in the human population. Now, more than 240 human cases of H5N1
infection have been reported.

Table 1 summarises the sequence of events following an outbreak

of H5N1 in Pakistan in October 2007.

Table 1. Sequence of events following an outbreak of H5N1 (Pakistan Oct 2007)

Relationship Onset Date Outcome Exposure Status
Case 1 (Index case) 29 Oct 07 Fully recovered Direct contact sick/dead poultry Confirmed (serology)
Case 2 12 Nov 07 Dead (19 Nov 07) Close contact with Case 1, Probable
no known direct contact with (No sample available)
sick/dead poultry

Case 3 21 Nov 07 Dead (28 Nov 07) Close contact with Case 1 and 2, Confirmed (PCR)
no known direct contact with
sick/dead poultry
Case 4 21 Nov 07 Fully recovered Close contact with Case 1 and 2, Confirmed (serology)
no known direct contact with
sick/dead poultry Source: WHO (2008)

Question .
What evidence is there that the virus was passed on directly from human to human?
Answer
Case 2,3 and 4 had no known contact with sick or dead poultry but all had close contact with the first sufferer (Case 1).

What if bird flu spreads in the UK?

The cosequences would be extremely serious (Fig 4)
Fig 4

Massive bird surveillance programme

Dead non-migratory swans in Scotland in 2006 were
confirmed to be infected with H5N1. 10km
surveillance perimeter established.

Dogs and cats must be kept inside

They are susceptible to the virus, as are big
cats in zoos.

Bird Flu
Mass vaccination
programmes
Poultry sales plummet Only if human-human
Despite the minimal risk, consumers transfer was proven
will shun chicken.

Pig movement banned

Piga can become infected with human
influenza. If they then picked up avain
influenza, there would be the risk of new
viruses emerging. The pig as a “mixing
vessel” is a huge threat.
No free-range chickens
Jamie Oliver’s campaign ruined. Any free range
farm near an outbreak would be closed down or
ordered to take chickens indoors.

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Treatment H5N1 inflenza virus hhas developed changes among the amino
Most H5N1 viruses that have caused human illness and death appear acids that make up its surface spikes of haemaglutinin
to be resistant to amantadine and rimantadine, two antiviral
medications commonly used for treatment of patients with influenza. haemagglutinin haemagglutinin
Scientists are investigating combinations of other anti-viral drugs (claude 1 H5N1) (claude 2 H5N1)
to test their effectiveness.
Positions at
In April 2007, the U.S. Food and Drug Administration (FDA) which the
announced its approval of the first vaccine to prevent human amino acids
infection with one strain of the avian influenza (bird flu) H5N1 virus. have been
altered
The vaccine was obtained from a human strain and consists of two
intramuscular injections, given approximately one month apart.
A clinical study was conducted to determine the appropriate vaccine
dose. 103 healthy adults received a 90 microgram dose of the vaccine
by injection followed by another 90 microgram dose 28 days later.
Another 300 healthy adults received a lower dose of the vaccine 48
people received a placebo injection.
The study showed that 45 percent of individuals who received the
90 microgram, two-dose regimen developed antibodies at a level
that is expected to reduce the risk of getting influenza. Although
all cases of bird flu in Indonesia outbreak
the level of antibodies seen in the remaining individuals did not
humans before 2005 2005
reach that level, current scientific information on other influenza
vaccines suggests that less than optimal antibody levels may still
have the potential to help reduce disease severity and influenza- Antigenic shift
related hospitalizations and deaths Refers to an abrupt, major change which results inan entirely new
influenza A virus subtype in humans.
Will there ever be a single flu vaccine?
Scientists used to dream of developing one vaccine that protects Antigenic shift can occur either through direct animal (poultry)-to-
against all known influenza viruses. It will probably never happen. human transmission or through mixing of human influenza A and
Here’s why: animal influenza A virus genes to create a new human influenza A
1. RNA is extremely error prone: on average, each new virus subtype virus through a process called genetic reassortment.
differs from its parent by at least one nucleotide. Antigenic shift results in a new human influenza A subtype. A global
2. Influenza is the only virus that undergoes true antigenic drift influenza pandemic (worldwide spread) may occur if three conditions
(genetic changes in the virus that occur because of errors in are met:
replication.) • A new subtype of influenza A virus is introduced into the human
3. Two different viruses can infect a cell at the same time. If population.
human and an avian flu virus infect a pig cell, they can swap • The virus causes serious illness in humans.
genes. This swap results in a new flu subtype that has both • The virus can spread easily from person to person in a sustained
avian and human flu characteristics. manner.

These genetic changes may result in changes to the types of
antigens on the surface of the virus. If these change, any existing
vaccine will not fit with them – a new vaccine will be needed.
Mutating viruses
Influenza A viruses are continuously evolving in two different ways:
antigenic drift and antigenic shift.
Antigenic drift
Refers to small, gradual changes that occur through point mutations
in the two genes that contain the genetic material to produce the
main surface proteins, hemagglutinin, and neuraminidase. These
point mutations occur unpredictably and result in minor changes to
these surface proteins.
Antigenic drift produces new virus strains that may not be
recognized by antibodies to earlier influenza strains. This is one of
the main reasons why people can become infected with influenza
viruses more than once.
The H5N1 virus in Asia and Europe meets the first two conditions:
it is a new virus for humans (H5N1 viruses have never circulated
widely among people), and it has infected more than 300 humans,
killing half of them.
However, the third condition, the establishment of efficient and
sustained human-to-human transmission of the virus, has not
occurred..
1918 Flu (H1N1) versus Avian Flu (H5N1)
• Jefferey Taubenberger and his colleagues have sequenced
the 1918 virus using frozen and autoposied lung tissue
• The 1918 virus is more similar to that of the avian flu than the
other viruses out there
• Terrence Templey and colleagues created a 1918 (H1N1)
reconstructed virus
• When mice were infected with this reconstructed virus, they
died within 3 days of infection
• Researchers plan to use these data to further understand
the nature of the avian (H5N1) virus in hopes of combating
any pandemic that may ensue

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Predicting the spread of bird flu These peaks in congregation of ducks indicate periods in which
Scientists have investigated a series of outbreaks of H5N1 which there is an increase in the chances for virus release and exposure.
occurred in Thailand and Viet Nam between early 2004 and late This allows health officials to predict where and when H5N1
2005. outbreaks are likely to occur.

The scientists constructed a computer model that considered how
different factors, including the numbers of ducks, geese and
chickens, human population size, rice cultivation and local
geography contributed to spread of the virus. The numbers of ducks
and people, and the extent of rice cultivation emerged as the most
significant factors.
Ducks feed mainly on leftover rice grains in harvested paddy fields,
so free-ranging ducks in both countries are moved to many different
sites according to where rice is being harvested.
In Thailand, for example, the proportion of young ducks in flocks
was found to peak in September-October. These rapidly growing
young ducks benefit from the peak of the rice harvest in November-
December.
In Thailand during 2005, farmers had to provide a health certificate
for their ducks and long-distance duck travelling was greatly
reduced.The local movements of ducks decreased when the
government started to support in-door keeping of ducks, offering
feed subsidies and construction of enclosures. Together, these
measures stopped the H5N1 transmission cycle and, since late 2005,
Thailand has suffered only sporadic outbreaks.
Viet Nam started nationwide vaccination of all poultry at the end of
2005 and it was repeated in 2006/07. Initially, human infections
disappeared and levels of disease in poultry fell noticeably. Only
gradually did H5N1 viruses re-appear, mostly in unvaccinated ducks.
Eventually, the scientists hope their predictive mapping will replace
indiscriminate mass vaccination.

Practice Questions
1. Read the account and answer the questions that follow.
What is bird flu?
According to The World Health Organization of the 378 people who are known to have been infected by the H5N1 strain of avian
influenza, 234 have died.
In a normal year, between 12 000 and 18 000 people die in Britain from normal flu.
In the UK, the government have started preparing for an epidemic of modified bird flu. They plan to buy nearly 15 million courses of an
antiviral drug called Tamiflu. Experts say that the government should order supplies of the vaccine against the normal bird flu that is
present in Asia. However, this might not work against a modified bird flu virus. To make matters worse, the main vaccine factory in
Britain has been closed for a while when microorganisms contaminated the vaccine. Animal-rights protesters have also targeted the
factory.
To produce the vaccine, bird flu virus is first weakened and is then grown on hens eggs. Genetic material from the virus is extracted and
mixed with genetic material from other known strains. The vaccine is then tested on rodents and then humans.
(a) (i) Calculate the percentage of infected individuals that died of avian flu. (2)
(ii) Explain how a vaccine could protect people from normal bird flu.
(iii) Suggest why animal-rights protesters are targeting the vaccine factory.
(b) The article says that the normal bird flu vaccine may not work on a modified bird flu virus. Describe how a modified bird flu virus may
be formed.
(c)Tamiflu is not an antibiotic. Why can’t bird flu be treated with antibiotics?
(d) The government believes that they will need to inform people of the dangers of modified bird flu to encourage them to have the
vaccine. Otherwise, the vaccination may have to be compulsory.
Explain why some people feel that they should be allowed to choose whether to have a vaccination or not.

Markschemes
1. (a) (i) 234/378; = 61.9%;
(ii) Vaccine contains a weakened virus;
Stimulates the body to make antibodies;
Antibodies/memory cells stay in the blood;
Full strength virus is destroyed rapidly;
(iii) The factory is using animals to produce / test the virus;
They believe that it is cruel to the animals;
(b) A person catches both bird flu and normal flu;
Genes from the two viruses are exchanged;
(c) Antibiotics only work on bacteria / Antibiotics don’t work
on viruses;
Viruses live inside living cells/antibiotics cannot reach them;
(d) Can give a person a mild form of the disease;
Some vaccines have been linked to side effects;
e.g. rashes;
It is their right to choose for themselves:
Acknowledgements:
This Factsheet was researched and written by Kevin Byrne.
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