A Planet of Viruses - Carl Zimmer (2011)

OLD COMPANIONS

Looking Down from the Stars

Influenza Virus

Influenza. If you close your eyes and say the word aloud, it sounds lovely. It would make a good name for a pleasant, ancient Italian village. Influenza is, in fact, Italian (it means influence). It is also, in fact, an ancient name, dating back to the Middle Ages. But the charming connotations stop there. Medieval physicians believed that stars influenced the health of their patients, sometimes causing a mysterious fever that swept across Europe every few decades. And ever since, influenza has raged through our species. In 1918, a particularly virulent outbreak of the flu killed an estimated fifty million people. Even in years without an epidemic, influenza takes a brutal toll. Each winter, thirty-six thousand people die of the flu in the United States alone; somewhere between a quarter million and a half million people die worldwide. Today scientists know that influenza is not the work of the heavens, but of a microscopic virus. Like cold-causing rhinoviruses, influenza viruses manage to wreak their harm with just ten genes. They spread in the droplets sick people release with their coughs, sneezes, and running noses. A new victim may accidentally breathe in a virus-laden droplet or pick it up on a doorknob and then bring now-contaminated fingers in contact with their mouth. Once a flu virus gets into the nose or throat, it can latch onto a cell lining the airway and slip inside. As flu viruses spread from cell to cell in the lining of the airway, they leave destruction in their wake. The mucus and cells lining the airway get destroyed, as if the flu viruses were a lawn mower cutting grass.

In healthy people, the immune system is able to launch a counterattack in a matter of days. In such cases, the flu causes a wave of aches, fevers, and fatigue, but the worst of it is over within a week. In a small fraction of its victims, the flu virus opens the way for more serious infections. Normally, the top layer of cells serves as a barrier against a wide array of pathogens. The pathogens get trapped in the mucus, and the cells snag them with hairs, swiftly notifying the immune system of intruders. Once the influenza lawnmower has cut away that protective layer, pathogens can slip in and cause dangerous lung infections, some of which can be fatal.

For a virus that has caused so much death in the past, and which continues to claim so many victims each year, influenza virus remains surprisingly mysterious. Seasonal flu is most dangerous for people with weak immune systems that can’t keep the virus in check—particularly young children and the elderly. But in flu pandemics, like the 1918 outbreak, people with strong immune systems proved to be particularly vulnerable. Scientists don’t know why the flu switches targets this way. One theory holds that certain strains of the flu provoke the immune system to respond so aggressively that it ends up devastating the host instead of wiping out the virus. But some scientists doubt this explanation and think the true answer lies elsewhere. Scientists also don’t know when influenza viruses first started making people sick. There certainly are historical records of outbreaks of deadly fevers going back thousands of years, but it’s impossible to know whether influenza viruses caused them, or another species of virus with similar symptoms.

Amidst all the mysteries of the flu, the origin of the virus is clear. It came from birds. Birds carry all known strains of human influenza viruses, along with a vast diversity of other flu viruses that don’t infect humans. Many birds carry the flu without getting sick. Rather than infecting their airways, flu viruses typically infect the guts of birds; the viruses are then shed in bird droppings. Healthy birds become infected by ingesting virus-laden water.

Sometimes strains of bird flu jump the species barrier and become human viruses. But for every successful transition, there are probably many failed crossings. Bird flu viruses are well adapted to infecting their avian hosts and reproducing quickly inside them. Those adaptations make them ill-suited to spreading among humans. Starting in 2005, for example, a strain of flu from birds called H5N1 began to sicken hundreds of people in Southeast Asia. It is much deadlier than ordinary strains of seasonal flu, and so public health workers have been tracking it closely and taking measures to halt its spread. For now, at least, H5N1 can only move from a bird to a human; it cannot move from one human to another.

Unfortunately, a poorly adapted flu virus can evolve into a well-adapted one. Flu viruses are particularly sloppy at replicating their genes, so many new viruses acquire mutations. These mutations are like random changes to the letters in the flu’s recipe. Some of the mutations have no effect on viruses. Some leave them unable to reproduce. But a few mutations give flu viruses a reproductive advantage. Natural selection favors these beneficial mutations, and flu strains can become better at infecting humans as mutation after mutation accumulates. Some mutations help the virus by altering the shape of the proteins that stud the virus shell, allowing them to grab human cells more effectively. Other mutations help the flu virus cope with human body temperature, which is a few degrees cooler than that of birds.

Human influenza viruses have also adapted to a new route from host to host. In birds, the viruses travel from guts to water to guts. In people, the virus moves from airways to droplets to airways. This new route also causes the flu rise and fall with the seasons. In places like the United States, most flu cases occur during the winter. According to one hypothesis, this is because the air is dry enough in those months to allow virus-laden droplets to float in the air for hours, increasing their chances of encountering a new host. In other times of the year, the humidity causes the droplets to swell and fall to the ground.

When a flu virus hitches a ride aboard a droplet and infects a new host, it sometimes invades a cell that’s already harboring another flu virus. And when two different flu viruses reproduce inside the same cell, things can get messy. The genes of a flu virus are stored on eight separate segments, and when a host cell starts manufacturing the segments from two different viruses at once, they sometimes get mixed together. The new offspring end up carrying genetic material from both viruses. This mixing, known as reassortment, is a viral version of sex. When humans have children, the parents’ genes are mixed together, creating new combinations of the same two sets of DNA. Reassortment allows flu viruses to mix genes together into new combinations, as well.

As scientists get a closer look at the genes of flu viruses, they’re discovering that reassortment has played a major role in the natural history of the flu. A quarter of all birds with the flu have two or more virus strains inside them at once. The viruses swap genes through reassortment, and as a result they can move easily between bird species. And sometimes, on very rare occasions, an avian influenza virus can pick up human influenza virus genes through reassortment. That can be a recipe for disaster, because the new strain that results can easily spread from person to person. And because it has never circulated among humans before, no one has any defenses that could slow the new strain’s spread.

Reassortment is important for other reasons than viruses jumping the species barrier. Once bird flu viruses evolve into human pathogens, they continue to swap genes among themselves every flu season. This ongoing reassortment allows the viruses to escape destruction. The longer a flu strain circulates, the more familiar it becomes to people’s immune systems, and the faster they can squelch its spread. But with some viral sex, an old flu strain can pick up less familiar genes and become harder to fight.

Humans are not the only hosts who have picked up flu viruses from birds. Horses, dogs, and several other mammals have also picked it up. And in April 2009, the world became painfully aware that flu viruses also infect pigs. An outbreak of so-called swine flu jumped from pigs to humans. It first surfaced in Mexico and soon spread over the entire planet.

The history of this particular flu strain, called Human/Swine 2009 H1N1, is a tangled tale of genetic mixing and industrialized agriculture. Pigs seem to have just the right biology for reassortment; some of their receptors can easily accept human flu viruses, while other receptors welcome bird flu. Over the past century, pig farms have grown in size and density, so that flu viruses can easily move from host to host and swap genes with other strains. The oldest known swine flu strain emerged around the same time the 1918 pandemic strain entered humans; this so-called classical strain is still making pigs sick. In the 1970s a bird flu strain evolved in Europe or Asia into a new swine flu strain. A different pig-bird mix arose in the United States. And in the late 1990s, American scientists discovered a “triple reassortant” in pigs that mixed genes from all three flu strains.

Once scientists sequenced the genes of the new Human/Swine 2009 H1N1, they realized that it was the product of two different flu viruses: the triple reassortant and a Eurasian bird-to-pig strain. By comparing the new mutations that had arisen from the viruses infecting different patients, researchers have estimated that this new virus first evolved in the fall of 2008. It circulated quietly before coming to light in the spring of 2009.

Because Human/Swine 2009 H1N1 was such a new virus, public health authorities swung quickly into action. The Mexican government essentially shut down the entire country for a time, hoping to prevent the virus from finding new hosts. As Human/Swine 2009 H1N1 turned up in other countries, their governments took actions of their own. By May 2009, it was clear that while the new virus was unusually swift, it was not significantly more dangerous than typical seasonal flu.

As I write in 2010, no one can say if the new strain will fade away, outcompeted by other flu strains, or if it will mutate into a more dangerous form, or experience even more reassortment and pick up new genes. But we are not helpless as we wait to see what evolution has in store for us. We can do things to slow the spread of the flu, such as washing our hands. And scientists are learning how to make more effective vaccines by tracking the evolution of the flu virus so they can do a better job of predicting which strains will be most dangerous in flu seasons to come. We may not have the upper hand over the flu yet, but at least we no longer have to look to the stars to defend ourselves.

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