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Number 200www.curriculum-press.co.uk

The Biology of bird fluBird flu isnt 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 isnt on the specs,

doesnt mean it wont 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.)

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 ingeneral 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.

QuestionHow would we name an avian flu virus with hemagglutinin

molecule 3 and neuraminidase molecule 2?

Answer : H3N2

2

2

1

1 1

1

11

11 HA (Hemagglutinin)

N (Neuraminidase)

1

2

abbreviated H or HA

"key" to gaining access

into the host cell

plays a singnificant role

in membrane fusion

abbreviated N or NA

needed for the newly replicated viruses to

leave the host cell so acts as "scissors"

M2 M1

RNPs

NS2

Also on the surface of the virus are M2 proteins, which

allow the virus to adjust its interior acidity.

Fig 1. H5N1 virus

N

HA

Influenza viruses - structure

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www.curriculum-press.co.uk

200. The Biology of bird flu

Fig 2. How the avian virus attacks

1. Attachment

The hemagglutinin (HA) protein spikes bind

to the surface of a cell. Specifically, they bind

to three sialic acid molecules on the surface

of the cell membrane

cell membrane

proton pump

HA proteinprotons

RNA

1

2

2. Endocytosis

The virus is enveloped in

a capsule made from the

cells membrane and

enters the cell by

endocytosis

3

3. Acidfication

Once inside, the

viruss M2

protein pumps

hydrogen ions

into the capsule,

to make it more

acidic. The fall in

pH induces a

dramatic change

in shape of thehemagglutinin

protein.

44. Apposition

The hemagglutinin bends

and pulls the virus capsule

towards the endosome

membrane.

5

5. RNA ReleaseWhen the capsule becomes acidic

enough, the virus capsule merges with the

endosome. Eventually, a hole is formed.

The viral RNA enters the cytoplasm and

migrates to the cells nucleus where the

virus copies its RNA

7. The new viruses then attach themselves

to new cells, starting the process of

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.

6. Newly assembled viral particles are released

from the cell, in a process known as budding.

Eventually, the cell dies off.

cytoplasm

Nucleus

Budding

packaging

Release Attachment

Endocytosis,

AcidificationTranslation

Post-translational processing

Fusion/

uncoating2 3

45

1

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H5N1Influenza 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.

Estonia

Russia

Poland

Denmark

Germany

HungaryAustria

Italy

Switz.France

Bulgaria

Bosnia

Turkey

Egypt

Greece

Israel

Albania

Black Sea

Mediterranean Sea

Lithuania

Romania

UK

The H5N1 virus has now

infected humans in Azerbaijan,

Cambodia, China, Djibouti,

Egypt, Indonesia, Iraq, Lao

Peoples Democratic Republic,

Myanmar, Nigeria, Pakistan,

Thailand, Turkey, and Vietnam.

It is a very dangerous disease.

As of 3rd April 2008, of the 378

people confirmed infected by

the World Health Organisation

(WHO), 238 had died. This

makes bird flu especially deadly

compared to other flu viruses.

A Brief History of

Influenza Pandemics1918 Flu Pandemic, or the

Spanish Flu

20 50 million deaths

world-wide more than

the casualties fromWWI itself

1957 Asian Flu Pandemic

2 million deaths

1968 Hong Kong Flu

Pandemic

1 million deaths

2006 Avian Flu ??

WHO reports 373

confirmed human

cases since 2003,

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 birds

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.

Influenza A viruses normally seen in one species can sometimes

cross over and cause illness in another species. For example, until

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, buta 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.

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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 H5N1infection 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 poultrySource: WHO (2008)

What if bird flu spreads in the UK?The cosequences would be extremely serious (Fig 4)

Bird Flu

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.

Poultry sales plummet

Despite the minimal risk, consumers

will shun chicken.

Mass vaccination

programmes

Only if human-human

transfer was proven

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 Olivers campaign ruined. Any free range

farm near an outbreak would be closed down or

ordered to take chickens indoors.

Fig 4

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 Aviruses.

Question.What evidence is there that the virus was passed on directly from human to human?

AnswerCase 2,3 and 4 had no known contact with sick or dead poultry but all had close contact with the first sufferer (Case 1).

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TreatmentMost H5N1 viruses that have caused human illness and death appear

to be resistant to amantadine and rimantadine, two antiviral

medications commonly used for treatment of patients with influenza.

Scientists are investigating combinations of other anti-viral drugs

to test their effectiveness.In April 2007, the U.S. Food and Drug Administration (FDA)

announced its approval of the first vaccine to prevent human

infection with one strain of the avian influenza (bird flu) H5N1 virus.

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

the level of antibodies seen in the remaining individuals did not

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-

related hospitalizations and deaths

Will there ever be a single flu vaccine?Scientists used to dream of developing one vaccine that protects

against all known influenza viruses. It will probably never happen.

Heres why:

1. RNA is extremely error prone: on average, each new virus

differs from its parent by at least one nucleotide.2. Influenza is the only virus that undergoes true antigenic drift

(genetic changes in the virus that occur because of errors in

replication.)

3. Two different viruses can infect a cell at the same time. If

human and an avian flu virus infect a pig cell, they can swap

genes. This swap results in a new flu subtype that has both

avian and human flu characteristics.

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 virusesInfluenza 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 influenzaviruses more than once.

Antigenic shiftRefers to an abrupt, major change which results inan entirely new

influenza A virus subtype in humans.

Antigenic shift can occur either through direct animal (poultry)-to-

human transmission or through mixing of human influenza A and

animal influenza A virus genes to create a new human influenza A

subtype virus through a process called genetic reassortment.

Antigenic shift results in a new human influenza A subtype. A globalinfluenza pandemic (worldwide spread) may occur if three conditions

are met:

A new subtype of influenza A virus is introduced into the human

population.

The virus causes serious illness in humans.

The virus can spread easily from person to person in a sustained

manner.

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..

Positions atwhich the

amino acids

have been

altered

haemagglutinin

(claude 1 H5N1)

haemagglutinin

(claude 2 H5N1)

H5N1 inflenza virus hhas developed changes among the amino

acids that make up its surface spikes of haemaglutinin

all cases of bird flu in

humans before 2005

Indonesia outbreak

2005

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 fluScientists have investigated a series of outbreaks of H5N1 which

occurred in Thailand and Viet Nam between early 2004 and late

2005.

The scientists constructed a computer model that considered howdifferent 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.

These peaks in congregation of ducks indicate periods in which

there is an increase in the chances for virus release and exposure.

This allows health officials to predict where and when H5N1

outbreaks are likely to occur.

In Thailand during 2005, farmers had to provide a health certificatefor 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 replaceindiscriminate mass vaccination.

Practice Questions1. 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 thefactory.

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 cant 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.

Acknowledgements:

This Factsheet was researched and written by Kevin Byrne.

Curriculum Press, Bank House, 105 King Street, Wellington, Shropshire, TF1 1NU.

Bio Factsheets may be copied free of charge by teaching staff or students, provided that their school is a registered

subscriber. No part of these Factsheets may be reproduced, stored in a retrieval system, or transmitted, in any other

form or by any other means, without the prior permission of the publisher. ISSN 1351-5136

Markschemes1. (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 dont 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:

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