New ways to flight the flu

You go to bed feeling fine. The next morning you’re sick with a fever, exhaustion, headache, body aches and more.

You may have influenza, better known as the flu. It’s caused by a virus, a tiny bit of genetic material surrounded by a protein. Flu viruses infect the nose, throat and lungs. (If people claim to have “stomach flu,” they are mistaken. They really have some other infection.)

Every year, between 5 percent and 20 percent of all Americans come down with the flu. Those numbers come from the U.S. Department of Health and Human Services in Washington, D.C. Complications send more than 200,000 of these flu victims to the hospital each year. Worse, the flu kills anywhere from 3,000 to 49,000 people annually — and that’s just in the United States.

The 1918 flu pandemic filled hospitals. In the United States alone it killed an estimated 675,000 people — more than died in World War I.

A widespread outbreak of flu or another infectious disease is called an epidemic. In some years, flu spreads so far and so fast that it causes a worldwide epidemic. This is known as a pandemic. Researchers hope to prevent a pandemic if possible. One tactic: vaccines.

Flu vaccines offer people some immunity. Immunity is the body’s ability to resist a particular disease by making proteins called antibodies. A vaccine can give that process a head start. However, no vaccine yet can fight all types, or strains, of flu.

What’s more, notes David Morens, “Flu is not one virus. It’s many, many viruses.” Morens works at the National Institutes of Health in Bethesda, Md. As an epidemiologist, he studies the causes, patterns and effects of disease in populations.

Flu viruses constantly evolve. That means their genes undergo change. Those changes are called mutations. And some mutations can let a virus evade any immunity, says Morens. Each year, the flu vaccine is updated to keep up with those mutations. The vaccine targets strains based on what health experts saw happening with different strains the previous flu season.

Health experts swab a chicken for evidence of bird flu at a market in Bangkok, Thailand. Chickens can host the virus, often without showing signs of disease.

Recently, an usually high percentage of changes happened in one type of flu virus, known as H3N2. As a result, the vaccine for the 2014 to 2015 flu season didn’t work well. In fact, the vaccine was only about one-third as effective as a well-matched vaccine would have been. Scientists from the Centers for Disease Control and Prevention and other organizations reported the results this past January 16 in Morbidity and Mortality Weekly Report.

Recently, health officials decided the vaccine for the upcoming flu season in the United States will include the H3N2 “Switzerland” type that made this year’s vaccine a poor match. It will have a new “Type B” strain as well. But new mutations keep occurring. Vaccines are “always a little behind,” Morens notes.

Now science aims to get ahead of the flu. Some researchers are trying to gauge how flu evolves. These experts want to know what strains are likely to strike hard and soon. Others are searching for vulnerabilities common to all types of flu. Still other scientists are looking for ways to stop new flu strains before they can easily infect people at all.

Constantly evolving

Katia Koelle is a biologist at Duke University in Durham, N.C. She says that one reason researchers have trouble keeping up with new flu types is the fact that these infections are caused by an RNA virus. RNA is short for ribonucleic (RY-boh-nu-KLAY-ic) acid. Cells grow and act by making specific chemicals called proteins. Cells do so at the right time and the right place with a type of RNA.

Like that RNA, a flu virus has a single strand of genetic material. Once in host cells, the virus gets the cell to copy its genetic code over and over to make more virus.

But “mutations arise all the time in flu,” Koelle notes. Here is one big reason: RNA viruses “don’t have proofreading mechanisms.” So they don’t detect a mistake and correct or eliminate mistakes that copying errors introduce. If the error doesn’t kill the virus, the affected RNA will show up in future generations. Such errors will get copied over and over whenever the virus reproduces. It’s like a printing press spitting out thousands of newspapers with the same misspelled headline.  

Computer-produced illustration of the structure of a flu virus. The white coil in the center is its genetic material: ribonucleic acid (RNA). The outer casing, called a capsid, is shown in purple.

That’s different from DNA viruses, a family that includes the one that causes chickenpox. When DNA reproduces, each bit on its double strands can partner only with a specific part on the other. It’s like a zipper. Each half has to pair with the other half. If there’s a snag, the process stops. Without that check, RNA viruses can get “sloppy,” Koelle says.

Researchers want better ways to predict which flu strains will hit people hardest next year. To do that, researchers at the University of Cologne in Germany and Columbia University in New York City have made a computer model. This computer program has equations, program instructions and data for thousands of strains of H3N2 (a common flu type).

The team focused on the gene for a protein found on the surface of the flu virus. That protein ishemagglutinin, or HA. HA helps the flu virus hook onto host cells. Antibodies can prevent HA’s action. But those antibodies work only if they can latch onto HA just right. Think of it as a matching lock and key set.

The researchers asked the computer model to sift through and find those strains least likely to encounter matching antibody “keys.” If few antibodies could lock up these virus strains, most people would be at risk of becoming infected by them.

“Basically, the rarer it’s been in the past, the better” a flu strain will do, says Koelle. She reviewed this study that used computer modeling before Nature published it in March. If new vaccines targeted those strains, the vaccines would equip more people with effective antibodies. Fewer people should then get sick from those strains.

Of course, new flu strains will still evolve. But the hope is that each year’s modeling will flag them early.

How viruses morph

Koelle also uses computer modeling to study how viruses evolve. Some mistakes in copying the RNA code can doom a virus. But about 8 percent to 10 percent of those RNA changes help the virus survive, she says. These survivors might then infect more people.

Other RNA changes are what Koelle calls “garbage” mutations. They don’t kill the virus. Still, these mutations can make the virus less likely to survive and reproduce. About 40 percent of mutations in RNA viruses fall into that “harmful” category, she says.

One of Koelle’s projects looks at links between “garbage” mutations and other mutations that give flu strains an edge. Remember that when the flu virus reproduces, all its genetic code gets copied, unless more mutations occur. Thus, an RNA change that helps a flu virus survive and spread means there will be more reproduction of its genetic code, including any “garbage” mutations. Koelle says it’s as if a bad student copies someone’s homework. That student will aim to copy everything, including both right and wrong answers.

Even though the “garbage” mutations carry forward into future generations, they might still “shape some patterns of evolution,” Koelle notes. For example, these changes might affect the rate of future mutations. Or the changes might affect where and how a virus spreads among people. Ideally, understanding the “garbage” could lead to new ways to fight flu.

Another computer-modeling project focuses on changes that might help the virus more quickly find host cells. “Once it’s in the host cell, an antibody can’t get it,” Koelle explains. Getting into host cells more quickly thus lets a virus strain “run and hide faster” from antibodies, she says. Computer modeling with data from work by other researchers could give clues about how those mutations work. Knowing that could help researchers figure out better ways to defeat the viruses with vaccines.  

Universal solutions?

Viruses can’t reproduce by themselves. Instead, they must invade the cells of another organism. Once inside, a virus turns the cells of its host into virus factories. Researchers are using another computer model to look at how that process starts. It focuses on the steps the HA protein goes through as it attaches to the outside of a new host cell.

“From experiments, we know that HA folds into two different structures— one before it connects [with a host cell] and one after,” explains Jeffrey Noel. He’s a biological physicist at Rice University in Houston, Texas. Noel and his team created a computer model that uses physics principles to figure out how the refolding happens.

On the outside of this flu virus are two different types of proteins (spikes). One — hemagglutinin, or HA — helps the germ find, latch onto and enter a cell. The second type will later let new copies of the virus exit the cell its parent virus had hijacked.

Before it latches onto a host cell, the HA protein can have any of several shapes. Again, some of those variations can keep antibodies from working. As noted before, the protein and antibodies must fit like a lock and key.

Meanwhile, the inner part of the HA protein pretty much stays the same from one type of flu virus to the next. “The virus can’t mutate that part of the protein very much,” Noel says. And it’s that inner part of the protein that lets the virus invade the cell.

As HA refolds, the protein exposes that inner part. Experts see this as a vulnerability. That exposure might be a chance “to go inside the fence and attack” the protein with a medicine, notes Noel. And since that part of the protein generally doesn’t change, such a medicine might work against many types of flu, he says. His team published its findings in the August 19, 2014, issue of the Proceedings of the National Academy of Sciences.

Still other research asks basic science questions about “what flu viruses do and how they do it,” notes Morens. For example, ducks and other birds naturally harbor flu viruses (often with no sign of disease). “How does a bird virus get to be a human virus?” he asks.

Changes that let flu viruses move from another species into humans are relatively rare. Yet those rare mutations pose big threats. When transfers happen, no one will have immunity for quite a while. If a new strain spreads very quickly among people, it risks becoming a pandemic.

Flu’s migrations

Flu doesn’t just move from birds to humans. Bird flu also can go to pigs or other mammals. Scientists at St. Jude Children’s Research Hospital in Memphis, Tenn., and other organizations found one form had infected harbor seals in 2011. That strain most likely came from a wild sea bird, notes Stacey Schultz-Cherry. She’s a virologist at the Memphis hospital.

Viruses infect animal cells by binding to sugars on their surface, or membrane, Schultz-Cherry explains. “These bird viruses typically can’t get into the cells” of mammals. That is because birds and mammals have different sugars on their membranes.

Schultz-Cherry compares it to trying to pick out someone in a crowd. If you’re told to “look for a guy in a yellow raincoat,” you know whom to look for. That is true even if you haven’t met the person before.

A woman receives the live influenza vaccine from a medical technician at a U.S. Army clinic. Vaccines delivered into the nose are recommended only for healthy people between the ages of 2 and 49, and not for pregnant women or other people with certain health conditions.

In this case, though, the bird virus changed. It found a way to recognize the sugar on seal cells. Nature Communications reported her team’s findings on September 3, 2014.

“No human illness was linked to the 2011 harbor seal virus,” Schultz-Cherry says. However, scientists think infected seals did transmit flu to people in the 1880s. And flu can indeed pass into people from other types of mammals. Flu also can go from people into other mammals — and maybe even back again. A study in the August 2014 Journal of Virology showed that human flu can infect dogs, for example.

“There must be some kind of host-switching process,” Morens says. But right now, “we have no idea how that happens.”

For one thing, genetically, bird viruses look very different from human viruses. Also, a virus can’t survive long outside a cell. Scientists are now scouting for various in-between hosts. But with so many strains and mutations, finding a host-jumping virus can be like looking for a needle in a haystack.

Lab studies can explore, in a more orderly way, how flu viruses evolve. Some studies start with a bird flu virus and work forward. Researchers alter the virus’s genetic code and see whether the change lets the virus infect a mammal, such as a ferret. 

Other lab studies work backward. Suppose your research team finds 100 differences between a human virus and the bird virus that was its likely source. “Then you start one by one getting rid of each mutation and see what happens,” says Morens. How does each change to the virus affect its ability to infect human cells?

Repeating the process over and over could show steps in the host-jumping process. “We want to know what those steps are,” says Morens. That will provide a general picture “of how the evolution occurred.”

Once scientists know that, they might find a way to stop the process before people get sick. Meanwhile, other researchers continue the search for better vaccines. Perhaps you might help make some of these important discoveries. “We desperately need more people in science,” says Schultz-Cherry.

In the meantime, good health habits can cut our risk of becoming infected. “Wash your hands,” Schultz-Cherry recommends. And get your flu shot, she adds. Tell your family members to do the same. Eat healthy foods and get enough sleep too. These are ways all of us can help fight the flu.

Power Words

(for more about Power Words, click here)

antibody  Any of a large number of proteins that the body produces as part of its immune response. Antibodies neutralize, tag or destroy viruses, bacteria and other foreign substances in the blood.

Centers for Disease Control and Prevention, or CDC  An agency of the U.S. Department of Health and Human Services, CDC is charged with protecting public health and safety by working to control and prevent disease, injury and disabilities. It does this by investigating disease outbreaks, tracking exposures by Americans to infections and toxic chemicals, and regularly surveying diet and other habits among a representative cross-section of all Americans.

computer model  A program that runs on a computer that creates a model, or simulation, of a real-world feature, phenomenon or event.

epidemic  A widespread outbreak of an infectious disease that sickens many people in a community at the same time.

epidemiologist  Like health detectives, these researchers figure out what causes a particular illness and how to limit its spread.

equation  In mathematics, the statement that two quantities are equal. In geometry, equations are often used to determine the shape of a curve or surface.

evolutionary  An adjective that refers to changes that occur within a species over time as it adapts to its environment. Such evolutionary changes usually reflect genetic variation and natural selection, which leave a new type of organism better suited for its environment than its ancestors. The newer type is not necessarily more “advanced,” just better adapted to the conditions in which it developed.

evolve  To change gradually over generations, or a long period of time. In living organisms, the evolution usually involves random changes to genes that will then be passed along to an individual’s offspring. These can lead to new traits, such as altered coloration, new susceptibility to disease or protection from it, or different shaped features (such as legs, antennae, toes or internal organs).

gene A segment of DNA that contains the instructions for making a protein. Those proteins govern the behavior of a cell — or large groups of cells. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.

germ  Any one-celled microorganism, such as a bacterium, fungal species or virus particle. Some germs cause disease. Others can promote the health of higher-order organisms, including birds and mammals. The health effects of most germs, however, remain unknown.

hemagglutinin    A spike-shaped protein on the outside of influenza viruses. It is made from two different types of chain-shaped materials. One scouts for a particular sugar on the outside of a cell. When this chain finds it, hemagglutinin binds to the cell and enters it. The cell now tries to digest this invader with acid. But instead, the invader changes its shape (in response to that acid) and firmly locks onto the cell.

immunity  The ability of an organism to resist a particular infection or poison by producing and releasing special protective cells.

infection  A disease that can be transmitted between organisms.

influenza (or flu)   A highly contagious viral infection of the respiratory passages causing fever and severe aching. It often occurs as an epidemic.

mammal  A warm-blooded animal distinguished by the possession of hair or fur, the secretion of milk by females for feeding the young, and (typically) the bearing of live young.

mutation  Some change that occurs to a gene in an organism’s DNA. Some mutations occur naturally. Others can be triggered by outside factors, such as pollution, radiation, medicines or something in the diet. A gene with this change is referred to as a mutant.

outbreak   The sudden emergence of disease in a population of people or animals.

pandemic  An epidemic that affects a large proportion of the population across a country or the world.

pathogen  An organism that causes disease.

proteins  Compounds made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. The hemoglobin in blood and the antibodies that attempt to fight infections are among the better-known, stand-alone proteins. Medicines frequently work by latching onto proteins.

reservoir  A large store of something. Lakes are reservoirs that hold water. People who study infections refer to the environment in which germs can survive safely (such as the bodies of birds or pigs) as living reservoirs.

RNA  A molecule that helps “read” the genetic information contained in DNA. A cell’s molecular machinery reads DNA to create RNA, and then reads RNA to create proteins.

strains  (in biology) Organisms that belong to the same species that share some small but definable characteristics. For example, biologists breed certain strains of mice that may have a particular susceptibility to disease. Certain bacteria or viruses may develop one or more mutations that turn them into a strain that is immune to the ordinarily lethal effect of one or more drugs.

vaccine   A biological mixture that resembles a disease-causing agent. It is given to help the body create immunity to a particular disease.

virologist  A researcher who studies viruses and the diseases they cause.

virus   Tiny infectious particles consisting of RNA or DNA surrounded by protein. Viruses can reproduce only by injecting their genetic material into the cells of living creatures. Although scientists frequently refer to viruses as live or dead, in fact no virus is truly alive. It doesn’t eat like animals do, or make its own food the way plants do. It must hijack the cellular machinery of a living cell in order to survive.

World Health Organization  An agency of the United Nations, established in 1948, to promote health and to control communicable diseases. It is based in Geneva, Switzerland. The United Nations relies on the WHO for providing international leadership on global health matters. This organization also helps shape the research agenda for health issues and sets standards for pollutants and other things that could pose a risk to health. WHO also regularly reviews data to set policies for maintaining health and a healthy environment.

zoonosis    (plural: zoonoses) Any disease that originates in nonhuman animals and is later contracted by people. Many zoonotic diseases also spread among a host of non-human species. For instance, the type of swine flu that sickened people throughout the world in 2009 also infected marine mammals, including sea otters.