Influenza Virus: A tiny moving target (Page 2 of 2)
Background for Teachers (Page One)
About the Lesson (Page One)
National Science Standards (Page One)
Preparation (Page One)
Click here to view "The influenza virus life cycle", an interactive presentation.
Engage/Explore
In this section students begin thinking about key components of the viral replication cycle. They will learn that viruses are limited to infecting certain cells based on interactions between viral coat proteins and cell membrane proteins.
1. Find a space that will allow students to walk around (move desks, go outside, use the gym or the stage). Write the following rules on the board, or somewhere where students can see them:
- Gotcha! First time - give up token. Second time – give up token, count 25 and sit down.
- Be discreet!
2. Tell the students they are going to play “Viral Gotcha”. The rules are as follows:
- Each player takes two tokens and draws a slip assigning a cell type and password. Keep your cell type and password secret!
- All players stand up and move slowly around the room.
- As you approach other players, clasp hands and whisper your cellular identity (cell or virus) to the other player.
- If you are a virus, and you find a cell, state your password. The “cell” player will accept the password or say “no entry”. If you are a cell, any virus with a matching password can “infect” you. Viruses with passwords that do not match yours cannot infect you.
- If a “virus” finds a “cell” that accepts the password, the cell has to give the virus a token – quietly! This means the “cell” has been infected.
- If a “cell” is “infected” twice, then after giving the second virus a token, the cell player keeps moving around while counting to 25 (in his or her head) and then sits down.
- Each “immune cell” player will have a list of passwords he or she “recognizes”. When an “immune cell” meets a “virus” with a recognized password, the “virus” player has to give his or her tokens to the “immune cell”. A “virus” that is caught by an “immune cell” twice must count 25 in his or her head and sit down.
Allow students to play for 5-10 minutes, depending on how many are sitting down.
3. At the end, tally how many viruses and cells are left standing or “alive”. Ask the “live” viruses how many tokens they each acquired. Group cells together by type and password, and determine how many times each cell type was infected. Ask the “immune cells” how many viruses each of them caught. Write the answers on the board.
4. Ask the students what they notice about the results.
Guide the students to find answers to the following questions:
- Which did better, cells or viruses?
- Did a particular type of cell get infected more often?
- Did a particular type of virus infect more cells?
- Did a particular type of virus get caught by the immune cells more often?
Let students explore the results as independently as possible. The goal is for students to come to understand that viruses do not infect cells randomly, and that it is possible for a virus to avoid detection by the immune system.
One option, if time allows, is to run the game multiple times and see if the results vary.
5. Explain to the students that viruses cannot infect cells without the correct “password” although in real life, the password is actually a coat protein on the virus interacting with a membrane protein on the cell. Usually passwords are cell type specific, for example, HIV targets T cells, but some viruses have a broader range of host cells.
Explore/Explain
In this section, students explore viral structure and how the virus replicates.
6. Have students work in groups of two to three to build their own influenza virus. Give each group one plastic egg, eight strands of yarn, enough modeling clay to cover the egg, 8 paper clips or buttons, 8 pieces of drinking straw, 15-20 velcro “dots”, and 15-20 grains of rice.
In this model, the Velcro represents the hemagglutinin, and the rice represents the neuraminidase. The egg represents the coat proteins, M1 and M2, and the yarn represents the eight strands of the genome with the sliding buttons or paper clips as the polymerase. The pieces of straw represent the nucleocapsid protein. The two nonstructural proteins are not present in the virus; they are found only in infected cells.
You may wish to provide students with additional materials to allow them more creativity in building their virus.
7. Show students Figure 1. Influenza Virus, and have them watch the animation of the viral life cycle. This figure and animation will serve as their guide in constructing their own virus. In addition, they may wish to explore the following site: http://www.bact.wisc.edu/Microtextbook/index.php?name=Sections&req=viewarticle&artid=126&page=1.
The influenza virus is fairly simple. It is composed of a protein coat, with a membrane covering, which is punctuated by two proteins, hemagglutinin (H1-16) and neuraminidase (N1-9). These two proteins determine which host cells the virus can infect. Inside are 8 pieces of RNA, the coat proteins (M1 and M2), two nonstructural proteins (NS1 and NS2), a nucleic acid binding protein, also called the nucleocapsid (NP), and a polymerase composed of three proteins (PA, PB1, and PB2). The three polymerase genes, hemagglutinin, neuraminidase, and nucleocapsid protein are encoded on single strands of RNA. M1 and M2 are produced by different spicing patterns off of one piece of RNA, as are NS1 and NS2.
To infect a cell, the hemagglutinin must first bind a host protein, causing the virus to be phagocytized. Once inside the cell, M2 is involved in releasing the virus genome whereupon the genome moves to the host nucleus. In the nucleus, viral protein production is initiated and the genome is replicated. PA, PB1, and PB2 form the polymerase. The polymerase, nucleocapsid protein (NP), NS2 and M1 bind the pieces of RNA. Hemagglutinin, neuraminidase, and M2 are produced and localized to the host membrane. The nonstructural protein NS1 inhibits the host defense response. When enough components are prepared, M1 and NS2 guide the export of the genome to the cell membrane where the viral coat has assembled. The virus forms and leaves the cell. Neuraminidase plays a critical role in viral exit.
8. If desired, provide teams with Master 1.1 Cell Surfaces. Have students demonstrate to themselves that their virus will only interact with one type of cell.
Point out to students that this is very much not to scale. Another option is to make a similar display, closer to scale, on poster board and have students stick their viruses on the large display.
Explain/Elaborate
In this section, students will consider how a virus mutates, acquiring the ability to infect different cells.
9. Have students fill out Master 1.2 Classifying Influenza Viruses using the CDC web site. . Have students go over their results in teams or collect student responses and have a brief class discussion.
This is a Type A virus because only Type A is classified in subtypes. Subtypes of influenza virus are named for the version of hemagglutinin and neuraminidase they carry. H7N2 carries hemagglutinin version 7, and neuraminidase version 2. Usually, only H1N1, H1N2, H3N2 influenza viruses are found in humans. H7 is a subtype that is found in humans and wild birds. The most likely source of the H7N2 virus was the wild geese at the pond.
Hemagglutinin and neuraminidase change by antigenic drift – changes due to mutations caused by the influenza virus’ error prone polymerase. This generates different strains of virus which the immune system may not recognize. A new vaccine must be developed each year because of antigenic drift. The early sample was a similar strain to the one used for the vaccine. By the end of the flu season in 2005, enough antigenic drift had occurred to generate a new strain which was not included in the vaccine.
10. Tell students that a cell can be infected by more than one virus. Explain that in this exercise they will model what could happen when two influenza viruses infect a cell simultaneously.
11. Give each group a set of red viral genome cards and a set of black viral genome cards. Have one student in each group shuffle the cards and hold them face down so that the blue labels show. Another team member should choose 8 cards to assemble a complete genome including one each of the cards labeled HA, NA, M, NP, PB1, PB2, PA, and NS.
12. Have students flip the cards over and see if they were able to build a virus from a single source. Ask students to figure out the probability of selecting a genome from either the black set or the red set.
The odds of generating a genome that is completely red or completely black is 1/256. There is a ½ chance each time a card is picked, since each protein must be represented, or ½ x ½ x ½ x ½ x ½ x ½ x ½ x ½ = 1/2 8 =1/256.
13. Ask the students what the outcome of this exercise is in terms of viral genomes. If mixed viruses are generated, will they all be able to infect the same cell types? What happens if they can infect fewer cell types? More? What are some other possible outcomes?
The students should recognize that at many viruses produced under these circumstances will have mixed genomes. In some cases these mixed genomes are not viable, but in some cases they are. Sometimes the virus will be released, but be unable to replicate because it lacks compatible proteins. The mixed viruses might also acquire new traits, such as the ability to infect different cells or replicate faster. If the hemagglutinin or neuraminidase changes, this is called “antigenic shift”. This is the scenario scientists fear could lead to a pandemic – an H5N1 (avian flu) and some other influenza Type A virus infecting a human cell, allowing the H5N1 subtype to acquire the ability to pass from human to human. For more information go to: http://www.cdc.gov/flu/avian/gen-info/transmission.htm.
14. Tell students one way for H5N1, the avian flu virus, to develop into a pandemic is if an H5N1 virus infects a human cell simultaneously with a normal human Type A virus. The two viruses might shuffle components creating a deadly virus with the ability to spread rapidly in humans.
Sometimes this antigenic shift occurs in an intermediary host, such as pigs. It’s possible that this chance event will never occur for H5N1, but it will occur sometime for some other similar virus.
Evaluate
Students should understand the basics of viral infection and replication. Evaluate their understanding by asking them to apply this knowledge to design ways to prevent infection or replication, or by asking them to determine how a virus could develop resistance to anti-viral medications.
14. Tell students that they are members of the Centers for Disease Control Division of Viral and Rickettsial Disease. Their task is to design two ways to prevent influenza virus from causing disease in humans. Working in teams of three to four students, they will prepare an oral report or poster that explains their methods for prevention of disease. They must justify their methods based on what they know about viral structure and replication cycle.
This question is deliberately left open-ended to allow students to design various methods. All answers should be considered valid as long as they use the information they have learned about viral structure and replication. For example, “Thoroughly wash your hands” is valid if it is based on keeping the virus away from pathways into the body or the concept that the virus capsule can be damaged by soap. More technical approaches would include interfering with the viral-cell recognition step, inhibiting entry into the cell, or interfering with viral replication.
You may wish to have students develop a public awareness campaign and put up posters of their prevention and treatment suggestions. They may wish to create a flyer, a web site, or an article for the school paper. Make sure student suggestions are valid before allowing students to post them.
15. OR have students visit http://www.niaid.nih.gov/factsheets/fludrugs.htm where they will learn about the four antiviral drugs currently available. This page explains how each antiviral medication works. Have students explain in evolutionary terms how a virus develops resistance to a medication. What is the variation? What is the selective pressure? Do viruses evolve more or less quickly than other species, vertebrates for example? Why?
This is an example of microevolution, in which small changes enhance the ability of the organism to survive. Virus populations have high levels of variation first because the RNA polymerase is not very accurate, and secondly because the replication cycle is fast and third because each virus generates many offspring. The selective pressure is ability to enter cells before the immune system detects and destroys the virus, survive in hostile environments between hosts, and replicate quickly and effectively once inside the cell. Successful viruses will replicate more often than unsuccessful viruses, increasing the number of viruses in the population with the “successful” characteristics.
Evolution of viruses leads to some interesting questions as there is ongoing debate regarding whether viruses are alive. Computer programs that model evolution may be considered the equivalent of viruses, since they cannot survive outside the host (computer program), and they evolve rapidly. For further exploration of this idea, try the Avida site .
Master 1.2 Classifying Influenza Viruses
1. American Experience “Influenza 1918”
The story of the 1918 pandemic.
2. Secrets of the Dead “Case File: Killer Flu”
Modern scientists study the 1918 virus to understand the source of its virulence.
3. Centers for Disease Control
Basic Q&A, information for specific groups, and specific topics such as prevention and outbreaks.
4. World Health Organization (WHO)
Concentrates on the potential pandemic, with information about how a pandemic will affect the world.
Includes an interactive site for tracking bird flu, video reports, Q&A on bird flu, and various articles on “Background and Features” and “Fighting the Virus”.
6. National Institute on Allergies and Infectious Diseases
Information about flu drugs.
This material was developed by Kristin Jenkins for NESCent. For questions or comments on this material, please contact the developer at kjenkins@nescent.org.
The National Evolutionary Synthesis Center (NESCent) is funded by the National Science Foundation (NSF), award number 0423641.
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