LESSON 4.5 WORKBOOK. How do viruses adapt Antigenic shift and drift and the flu pandemic

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1 DEFINITIONS OF TERMS Gene a particular sequence of DNA or RNA that contains information for the synthesis of a protien or RNA molecule. For a complete list of defined terms, see the Glossary. LESSON 4.5 WORKBOOK How do viruses adapt Antigenic shift and drift and the flu pandemic As discussed in the last lesson, mutations are made randomly. If you take a test and randomly fill in the answers, do you think you will get them all right? No, but if you repeat your random answering thousands of times you might, and this is how mutations work. Many mutations are silent or harmful to the pathogen but the few that are helpful make the wait worth the waste. In this lesson we will further explore how viruses change and adapt. In particular, this lesson describes how the processes of antigenic drift (random mutation), and antigenic shift (swapping viral genes) lead to adaptations that keep viruses one step ahead of the immune system. Mutations in viruses can have one of three outcomes: 1. A mutation may have no effect on the virus structure and function. 2. A mutation may be unfavorable to the virus. 3. A mutation may be favorable to the virus. Even though we are talking about viruses here it is important to note that mutations also happen in the bacterial and parasitic pathogens we have discussed. This is an important process contributing to drug resistance and immune evasion! Figure 1: A mutation in a gene may not affect a protein (left panel) or can lead to changes in a protein (right panel) that may be favorable or unfavorable. 1. Mutations can have one of all of the following effects EXCEPT: The mutation may have no effect on the virus s ability to survive or become virulent. The mutation may produce a virus that is defective in some way. c. The mutation can create a virus that is more virulent. d. none of the above 176

2 DEFINITIONS OF TERMS Antigenic having the ability to be recognized by the immune system as foreign, and provoke the production of antibodies. Segmented genome a genome that is fragmented into multiple pieces instead of contained in one large molecule. For a complete list of defined terms, see the Glossary. LESSON READINGS Viruses mutate via antigenic drift and antigenic shift Antigenic drift is the name given to the random mutations that accumulate during replication As we saw in the last lesson, mutations in viral genomes, either DNA or RNA, can accumulate quickly because viruses often lack proofreading enzymes. This is why there is a high likelihood that new virus particles will have genomes coding for altered proteins. Such changes, may be detrimental or beneficial to the virus. For example, if the mutation leads to a change in the entry receptor protein of the virus, and it no longer binds to the host cell, oops, that virus is dead. However, if a mutation leads to change in a protein on the surface of the virus, it may make it unrecognizable to the host immune system, even if the host was exposed to a different version of the virus in the past. In fact, this is how viruses replicate successfully in a host they randomly guess on the test and then repeat this process enough times to ensure that one of them gets a perfect score. We have all felt the consequences of this process; antigenic drift is the major reason why we need a new flu vaccine every year. The flu virus is an RNA virus, and as we learned in lesson 4.4, RNA viruses can t proofread when copying their genomes. For this reason, RNA viruses are prone to high levels of mutations via antigenic drift. Hence, every year when the flu comes back around, it has drifted away from its previous form. Figure 3: Two strains of the same flu virus infect different cells in the respiratory tract. Figure 2: Comparison of antigenic drift and shift: minor vs. major changes. Antigenic shift or how one virus can exchange genes with another Unlike the process of accumulating single mutations through antigenic drift, antigenic shifts are much larger changes in the genome, and hence viral properties, that happen suddenly. However, only viruses with segmented genomes, like influenza, can do this. 2. Antigenic shift is to as antigenic drift is to. swapping viral genes; random mutation swapping genomes; random mutation c. random mutation; swapping genomes d. random mutation; swapping viral genes 177

3 DEFINITIONS OF TERMS Viral strain genetic variant of the same virus. For a complete list of defined terms, see the Glossary. LESSON READINGS As shown in the above picture, the influenza viral strain, H1N1, generally infects the mucosa of the upper respiratory tract, whereas a different strain, H5N1 (also known as bird flu), infects the mucosa of the lower respiratory tract. Infecting the lower respiratory tract causes a severe immune reaction, leading to the accumulation of fluid in the lungs, causing severe symptoms mimicking drowning. This ability to infect the mucosa of the lower respiratory tract is thought to be why H5N1 is more deadly than H1N1. On the other hand, the inability to infect the upper respiratory tract makes it harder for H5N1 to spread from person to person. But what if H1N1 and H5N1 could trade genes via antigenic shift? This could potentially make a virus that infects both the upper and lower respiratory tracts. This is why many scientists fear the flu over all other pathogens! Viruses with nonsegmented genomes can t undergo antigenic shift Now, let's answer the question: why viruses with nonsegmented genomes cannot undergo antigenic shift? In figure 4, the tan shape in the middle represents a host cell. Each blue pentagon depicts a virus. The blue, yellow, red and green stars on the blue pentagons represent viral surface proteins or receptors. The colored lines within each virus represent the viral genomes. Here, the genomes are in one piece, hence nonsegmented, and each color represents a different gene within the genome. In this case, when a host cell is infected by two strains of a viruses (A and B) at the same time, the genomes of both viruses will replicate in the cell. When the new viruses are assembled, each virus will have a genome identical to one of the parent viruses with the exception of any mutations that occurred by antigenic drift during replication. Viruses with segmented genomes can exchange genes by antigenic shift Figure 4: Nonsegmented viruses can't exchange genes even when they infect the same host cell. Now, let's see how segmented genomes can undergo antigenic shift. In figure 5, the shapes represent the same structures as above. This time though, the two viruses (C and D) have segmented genomes: composed of multiple pieces. When a host cell is infected with viruses C and D at the same time, the genomes of both viruses will replicate in the cell, but when the new viruses start to assemble the gene 3. Antigenic shift allows one virus to exchange genes with another virus. True False 178

4 LESSON READINGS Figure 5: Segmented viruses can exchange genes when they infect the same host cell. So the offspring of segmented viruses can contain genes from both parent viruses plus differ by antigenic drift. segments can get mixed up. Each new virus needs to have a certain number and type of segments to be functional. In this case that will be one large (in grey), one middle (green or yellow), and one small (blue or red) gene segment. But the new viruses assemble with a random combination of these segments, possibly generating a new type of virus with genes from both parent viruses. This is depicted in Fig. 5: the resulting new viruses have segments from both parent genomes the new viruses have swapped their middle size segments, green and yellow, creating progeny viruses that are very different from the parent types. To top that, they will also have any mutations they acquired by antigenic drift during replication! Will this swapping cause change in function? Probably. For example, the new viruses may acquire a new collection of entry receptors allowing them to infect a whole new set of cells think back to H1N1 and H5N1. H1N1 could quite conceivably acquire new entry receptors from H5N1 through antigenic shift when both viruses infected the same cell. Keep in mind that the depicted swapping is not the only possible one in reality the combinations are practically infinite. 4. In an antigenic shift, the resulting genome will contain only the parent genome. genomes not present from parent genomes. c. genomes from both parent genomes. d. all of the above 179

5 STUDENT RESPONSES H1N1 and H5N2 can undergo antigenic shift. The H and N genes are on independent gene segments. What variants of influenza could you get? Will the new viruses be more or less virulent? Remember to identify your sources Construct an explanation based on evidence for why adaptation does not occur in the absence of natural selection. 180

6 TERMS TERM DEFINITION Antigenic Gene Segmented genome Viral strain Having the ability to be recognized by the immune system as foreign, and provoke the production of antibodies. A particular sequence of DNA or RNA that contains information for the synthesis of a protein or RNA molecule. A genome that is fragmented into multiple pieces instead of contained in one large molecule. Genetic variant of the same virus. 181