Have you had the flu this season? If not, chances are you have taken precautions, such as getting a flu shot and vigilantly washing your hands. These strategies can effectively reduce your risk of infection, but they are not the whole story. Your body employs many defensive tactics too.

Intruders and Defenders

Under cover of darkness, an intruder silently slips into a warehouse of valuable machinery. Evading detection, the intruder passes through the warehouse and accesses the central command center. Within hours, the intruder has commandeered the machinery and set in motion a nefarious scheme.

Although it sounds like a trailer for the next blockbuster movie, this scenario describes a chapter in the life history of the influenza virus. The tiny virus can be thought of as an intruder scheming to gain access to the cells of your body, which are analogous to little warehouses of raw materials and machinery. After you inadvertently inhale a viral particle, perhaps set loose by the cough or sneeze of an infected friend or stranger, the virus infiltrates the cells of your respiratory tract and sets to work making more virus.

However, like in any good movie, the invader does not go unchallenged. Our bodies are equipped with an arsenal of defenses to combat infection. One key antiviral factor is known as interferon. Named for its ability to “interfere” with viral reproduction, interferon is a molecular signal released by cells when they are attacked by pathogens, including viruses. Interferon acts like an alarm bell, broadcasting the danger to other cells in the body and initiating an organized counterattack.

Although partly responsible for several familiar flu symptoms, such as aching muscles and fever, interferon is an important natural defense that ultimately helps you to feel better. In addition to activating immune cells, such as natural killer cells and macrophages, which attack invaders, interferon also boosts a cell’s ability to resist infection. How this enhanced resistance is conferred is a question of great interest.

A Tiny Godzilla

The influenza virus has had a significant impact on society for generations. There are actually several different types of influenza viruses, but the one that poses the biggest threat to humans is known as Influenza A. This virus – strains of which include the seasonal flu strains as well as H1N1 – is responsible for an estimated 36,000 U.S deaths each year. Ironically, the Influenza A virus itself is very, very small: only 80 to 120 billionths of a meter in diameter. That’s small even for a virus.

The virus is also surprisingly bereft of genetic material. It has only enough genetic material to code for 11 different proteins (humans make an estimated 2 million proteins!). Like all viruses, the Influenza A virus is so miniscule that it is not even capable of reproducing by itself. That’s why it needs us (or another suitable animal) to be its “host” and provide the cellular machinery to enable viral reproduction.

Identifying the protagonists

Scientists have long been interested in discerning which host proteins are commandeered by the Influenza A virus. Recently a team of scientists at Harvard Medical School and Yale University School of Medicine used a genetic screen to identify host proteins that modify the viral lifecycle. Using human cells grown in thousands of little dishes, they systematically eliminated the expression of nearly 18,000 human proteins using a technique called siRNA. They then exposed the cells to influenza virus and examined how the virus reacted to the absence of each of the host proteins. Did the virus survive better or worse? The scientists identified 120 proteins from the host cells that affected viral survival and reproduction. Some of these proteins were already known to play a role in viral infection, but many were completely novel.

In some of the host cells the virus had a field day, and viral infection rates soared. This observation suggested to the scientists that the proteins depleted in the host cells normally function to inhibit the virus. This reasoning was supported by the fact that when they reintroduced these proteins to the cell at even higher levels than normal, viral reproduction was severely impaired. The researchers chose to focus their attention on one of four proteins which restricted viral reproduction in this way, a protein called interferon inducible transmembrane protein 3 (IFITM3).

This particular protein caught the attention of the scientists because it was already known that the body’s alarm signal, interferon, increased the production of IFITM3, but not much else was known about it. The scientists wondered if perhaps IFITM3 could mediate the protective effects of interferon, which had long been known to enhance a host cell’s ability to resist infection. Indeed, they showed that without IFITM3, interferon was much less effective at promoting viral resistance, suggesting that IFITM3 is partly – but not completely – responsible for the protective effects of interferon.

Refining the Roles

At this point it is unclear how exactly the IFITM3 protein thwarts the Influenza A virus. However, the scientists showed that IFITM3 acts very early in the course of infection because it affects the ability of virus to access the host cell. This makes IFITM3 an intriguing therapeutic target because it serves as a first line of defense, deflecting the virus before it even enters the cell. As scientists learn more about this protein and the other antiviral proteins identified in their screen, they may be able to use the information to design drugs to target the early stages of viral infection.

New flu drugs are needed because the current ones are incompletely effective and subject to viral resistance as viral strains mutate. Just as bacteria can evolve ways to survive antibiotics, viruses can also develop resistance to antiviral medications. In fact, there have already been reports that a growing proportion of Influenza A virus strains (including H1N1) are resistant to commonly prescribed antiviral medications, such as Tamiflu(r).

Tamiflu (r), also known as Oseltamivir, does not prevent the flu virus from entering the cells of your body. Instead it works by preventing the virus from effectively reproducing once there. The drug blocks the activity of a viral enzyme called neuraminidase which is one of the essential tools in the virus’s toolkit. The virus needs this enzyme to release its progeny into the body. Therefore, by inhibiting neuraminidase, Tamiflu(r) limits the virus’s ability to infect other healthy cells, thus lessening the severity of the illness and also reducing its transmission to others.

Interestingly, this research might also inform drug development for viruses besides the flu. The scientific team found that not only did IFITM3 protect human cells from several Influenza A strains, including H1N1, it also defended against two other major human viruses, Dengue Virus and West Nile Virus. This suggests that IFITM3 is a versatile defender against at least three kinds of viruses. However, the protein’s antiviral powers are not universal: IFITM3 did not protect against HIV or the Hepatitis C virus.

This research has another potential application in addition to drug development: vaccine production. The traditional way of producing vaccines is slow and laborious, and is not well suited for rapid “scaling up” in response to a pandemic. Although alternative methods exist, most vaccines are currently produced within chicken eggs. After the eggs are injected with live virus, they then need to be incubated for a period of weeks or months while the virus propagates. Only then can the liquid inside the egg be removed and its potency analyzed.

Currently it takes one to two eggs to produce a single vaccine dose. But what if one could enhance viral reproduction within the egg and allow each egg to churn out enough material for multiple doses? Because IFITM proteins are found in many animals, including chickens, the scientists speculate that by inhibiting these proteins in the eggs, vaccine manufacturers could remove a natural block to virus reproduction. If so, this would make vaccine production more efficient, less costly, and better able to respond to worldwide demand. Although still in the future, advances like this might someday help thwart would-be viral invaders and bring us all one step closer to a happy ending.

–Kelly Dakin, Harvard Medical School

For More Information:

CDC Flu Guide :
< http://www.cdc.gov/flu/index.htm >

CDC statement on Tamiflu:
< http://www.cdc.gov/media/pressrel/2009/s090109.htm >

Previous SITN flash article discussing the Flu:
< https://sitn.hms.harvard.edu/sitnflash/html_archives/sitnflash-200906.html >

Primary Literature:

“The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus.” Brass AL, Huang I-C, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ. Cell. Published online Dec. 17, 2009.

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