AS NATURAL AS BREATHING
AS NATURAL AS BREATHING
The Flu Virus
Abstract and Keywords
This chapter discusses the flu virus. The virus that causes the annual epidemics of influenza travels through the air. Although flu is widely viewed as a human disease, its agent is by nature a virus of birds. Circumstances may force this avian virus to infect other animals, but it is most at home in wild ducks. Contact with wild birds or their excrement causes epidemics of flu virus infections in seals, whales, horses, chickens, turkeys, and pigs. The transmission of the flu virus to humans and flu epidemics are discussed.
The virus that causes our annual epidemics of influenza comes to us through the air. We think of the flu as a human disease, but its agent is by nature a virus of birds. Circumstances may force this avian virus to infect other animals, and it gets better and better at doing this. But it is most at home in wild ducks. Ducks are infected very young, and about 20 percent of any wild flock usually harbors this avian virus. It is endemic in ducks—a permanent feature of their world—but never makes them sick.
While our flu virus infects cells of the airways, the avian flu virus infects cells of the stomach and intestines. It enters birds when they drink water and is excreted with their feces. In lakes where ducks get ready for their annual migration, influenza virus is present in large quantities, and the little beaches around the lakes are full of very infectious excrement. However, once the birds migrate to warmer regions, their flu virus goes dormant. Preferring cooler weather, the virus dwindles to small quantities in the wintering ducks—but it breeds up again when they return to their home lakes.
Contact with wild birds or their excrement causes epidemics of flu virus infections with some regularity in seals, whales, horses, chickens, turkeys, and pigs. In contrast to what happens in a population of ducks, where the virus is constantly present, in these other animals the virus (p.14) is generally absent until it suddenly emerges. The same is true for people.
Flu epidemics in pigs are of most concern to us for several reasons. The flu virus cannot thrive long in a group of seals, whales, or other mammals that have very limited contact with each other. Its transmission is too dependent on intimate contact; pigs like living close together, so they sustain more flu epidemics. Also, pigs are a major food animal and in some countries, such as China, they are by far the main animal raised for meat. Compared with most other food animals, such as chickens and turkeys, pigs are large and expensive—so one stricken pig is a greater economic loss than quite a number of stricken fowl.
Our biggest source of concern is the fact that hog viruses can more easily infect people than the viruses of most other animals. Workers in slaughter houses regularly contract swine flu infections. Children are susceptible to viruses that seem to be a mixed form of bird, hog, and human viruses. And we must not only fear the true hog viruses but also those of other animals that happen to infect hogs—including the bird flu viruses.
Apparently transmission of the influenza virus from bird to pig makes it easier for the virus to take the trip to man. The flu viruses that annually plague us seem to arise in China where both ducks and pigs often live closely with small farmers. As in other very poor farming cultures, animals may even live in the house, especially when the weather gets too cold to keep them safely outside. One virus that arose this way caused the 1918 flu epidemic, though its history was not known for years. And while pigs make a good stepping stone from birds to humans, bird viruses can sometimes infect humans directly.
How does the versatile flu virus do so much damage? Although basically a bird virus, its disease strikes humans hard every winter, causing a worldwide epidemic—or pandemic—that varies in severity. It usually strikes in winter because in most places that season brings the conditions it likes: relatively cooler air with a low degree of humidity. The virus enters the human body through the airways as we breathe. Once inside, it immediately finds cells in which it can multiply: the cells of the epithelium or mucosal lining. Fever and inflammation result, and the irritated airways cause lots of coughing and sneezing. Only one out of every ten flu virus infections takes its course without us noticing that anything is amiss.
Flu becomes most serious when the virus attacks the smallest branches of the airways. It is most virulent in these cells located deepest in the lungs. In this area, it takes only a few virus particles to have a big effect, (p.15) since the cells have the highest density of receptors for the flu virus. The virus multiplies at a furious pace in a couple of days, by which time the mucus in the nose contains tens of millions of virus particles.
Transmission of the human flu virus takes place during the first week of infection. Flu patients are most contagious during the first three or four days of the illness. After a week, there are no more virus particles to be found, but by that time, they have been sneezed and coughed all over everyone nearby. They have been spread through the air by aerosol particles of mucosal fluid. This method of transmission makes the human flu virus more contagious than the duck virus, which is spread by water.
The clinical aspect of the flu—the eruptions of coughing and sneezing—thus contributes directly to the spread of the virus. And flu is an illness against which you cannot easily protect yourself by adapting your behavior. If you do not want to contract HIV infection, you can avoid unprotected sex or the use of injectable drugs, but the only way to avoid flu is to give up breathing. You could stay away from other people, but this is not easy.
Suppose you board a bus or train and sit down next to a perfectly healthy-looking person. He is not covered with spots, for example, as he would be with measles or smallpox. After awhile, he begins to cough and does not cover his mouth. Coughing does not prove he has flu but, even if it did, are you likely to change your seat? If you do, and the flu is going around, will your next seat companion be any healthier than the first one?
No other mammal is as mobile as man. For almost any virus, man is the ideal vehicle for getting disseminated all over the globe. Ducks can only take the flu virus between their two seasonal homes, but people can take it anywhere. And every person, of whatever age, sex or race, can get the flu. Adults spread it mainly by traveling, especially in airplanes. It is hard to imagine a better way of spreading the flu than by airplane travel. It can take an influenza virus to any corner of the earth within twenty-four hours.
In 1977, an airplane full of passengers had to operate without ventilation for about four hours. In that short period of time, 72 percent of the passengers got the flu from one fellow passenger who was coughing a lot. The virus cannot have spread in any way other than through the air, since the passengers hardly left their seats. And while that particular plane had a ventilation breakdown, many planes use only minimal ventilation systems all the time.
(p.16) However, the first infections in a flu outbreak do not usually take place on a plane. They take place among children in school, who take them home to brothers and sisters at home, to parents and grand-parents. By way of the adults, the virus then spreads from one location to another. Newborns and the elderly tend to be last infected, and the elderly in particular lose large numbers of their population to the flu.
Studies in Houston, Texas, have shown that during the average flu epidemic in the western world, 40 percent of young children and about 20 percent of the adults become infected. At least 90 percent of infected people have symptoms, but most never require medical attention. Nevertheless, some 20,000 people in the United States die from the flu every year. The rate of infection and morbidity, or disease, is highest for young children; but the rate of flu mortality is highest among the elderly, especially those with heart problems or cancer. Pregnant women too are at higher risk of flu death than the general adult population.
The epidemic of 1918 departed from the average in major ways. After three quarters of a century, it remains the worst ever to occur, causing death in 30 to 50 million people worldwide. The most conspicuous thing about the 1918 pandemic was that it particularly decimated people in the age group of 20 to 40 years—people who had just died by the millions in The Great War. Ultimately the epidemic claimed more victims in a short time than any other infection in the history of the world. Yet unlike plague, the flu was not usually a killer; it had always been an illness cured by staying in bed for a few days. People think of flu as simply a bad cold; indeed, in Italy it was originally called influenza di freddo (cold influenza). But 25 percent of the entire American and European populations contracted the flu in 1918, and one in every fifty died from its consequences.
The 1918 flu virus was far more virulent than any other before or since. The virulence of a virus has to do with the damage it can do: its capacity to cause illness and death. One school of thought holds that viruses do not benefit from being too virulent—from causing too much harm to their hosts, on whom they depend for their reproduction. This school of thought assumes that a virus and host eventually adapt to each other so that the initial, or acute, infection takes its course almost or entirely unnoticed. This theory is only partly correct. With the flu, the virus spreads strictly during the first week of infection, then begins its cycle in a new host. Thus the survival of this virus is not compromised by its virulence. Once the virus has moved on, it has no problem if the lungs in the old (p.17) host are reduced to an amorphous foaming mass, making it impossible to draw even the slightest breath.
In 1918, there were actually two influenza epidemics. The first occurred in the spring and was in no way different from a normal annual flu epidemic. The second occurred in the fall, with the tragic outcome that millions died all over the world. This disaster would become known as the Spanish flu, because the first few cases were reported from Spain. But as we will see, each year's flu virus actually arises in China and causes at least a small epidemic there before spreading abroad.
Largely unnoticed in the 1918 chaos was the fact that pigs also had a flu epidemic about that time. And ever since then, a swine epidemic of influenza has occurred nearly every year. Did we catch the flu from the pigs or did they catch it from us?
The latter now seems to be the case, though that discovery was years away in 1918. First the flu virus had to be discovered, which happened in the 1930s. Virological techniques had to be developed, so it was 1936 before researchers could replicate influenza viruses in the laboratory. To obtain sufficient numbers for systematic study, scientists would inject saliva containing the virus into the amniotic fluid which surrounds a chicken embryo. When breathing, the embryo takes in and expels this fluid. The virus thus grows in its lungs, although in nature a flu virus infects gastrointestinal cells in birds. Within two days, it would be possible to see if there was virus growing: the amniotic fluid would become non-transparent and opaque.
In 1944, the first Americans were vaccinated against the flu. The vaccine was based on that year's flu virus, which had been cultivated in chicken eggs, then “killed,” or de-activated. Like all vaccines based on killed virus, it contained enough viral substance to stimulate an antibody response but could not cause disease, because a killed virus cannot reproduce.
Since 1944, a routine has developed. Each year flu specialists watch for signs of the annual epidemic and its cause: the virus we need to fight. Then they race against time to cook up a vaccine based on that virus, hoping to be ready before the epidemic gets out of hand. In about 8 months, the vaccine has to be produced in hundreds of millions of dosages.
What made the 1918 flu virus so virulent is still mysterious, but continuing research has brought progress in our understanding. The answer remains important because at any time, the annual flu virus could turn out to be a killer of 1918 proportions. It would not be the same virus as (p.18) in 1918, but the more we know about that virus, the better we can manage each new one.
An early question for flu researchers was why that virus killed people 20 to 40 rather than older people. A simple answer was that people older than 40 had already survived an earlier infection with a similar virus. They were thus somewhat immune to it. This suggests that a 1918-like virus was present earlier and went unnoticed. Indeed, a search of records found that small flu epidemics had occurred in 1916 and 1917 in British army barracks in England and France.
An additional answer relates to a lethal sleeping sickness, encephalitis lethargica, which was described in 1917 by Baron Constantin von Economo. According to this Viennese physician, patients with the disease would sit motionless and mute. In 1982, Ravenholt and Foege, two scientists at the U. S. Centers for Disease Control (CDC) showed that living through a serious flu was directly associated with contracting encephalitis lethargica.
As often happens in science, they had found new implications in an old story. On November 7, 1918, a steamship from New Zealand landed in Western Samoa. Its crew brought influenza, and 8,000 West Samoans died from it in two months. When the nearby inhabitants of American Samoa heard about this, they sealed their island from the outside world and kept the flu out. During the 1919 to 1922 period, 79 Western Samoans died from von Economo's disease, but only 2 died in American Samoa.
The virus which caused the 1918 disaster was neuro-virulent: it had a preference for infecting brain cells in addition to airway cells. This characteristic could hold the key to predicting whether next year's flu virus might be the next 1918–like killer.
Getting back to the simple answer: if people over 40 were relatively immune to the 1918 flu, there must have been flu viruses circulating decades before that. Since all flu epidemics since 1918 have originated in China and, more specifically, in the southern Chinese province of Guangdong (formerly Canton), researchers looked to that province for earlier epidemics. Sure enough, the first flu epidemic ever described in detail took place in September 1888 in Guangdong. It is likely that there were even earlier ones, never recorded.
In any case, when influenza struck Guandong in 1918, it was no worse than any annual flu in the area. Moreover, it struck teenagers more than older people. The first finding suggests that people had earlier been struck by such a virus, so the population had some immunity. The second finding (p.19) suggests that immunity was strongest in that part of the population that was born in the second half of the 19th century.
How did the 1918 flu virus travel the world in those days before airplane travel? Nothing is documented, but Cantonese workers came by boat to France to dig trenches for the war, so perhaps one of them brought the flu. If so, the first European cases occurred in France, unnoticed, and were reported from a slightly later outbreak in Spain. Perhaps the flu then spread to North America with service men returning after the war.
Researchers began to suspect that the first truly human flu viruses originated early in the 19th century but did not become a threat until the early 20th century. What animal was its host before it became a human virus? The first step toward an answer was to identify the 1918 virus, using a phenomenon known today as original antigenic sin. Christians believe humans are marked by the “original sin” in the Garden of Eden. By analogy, we are all antigenically marked by our first flu infection. This usually occurs in childhood, and every subsequently occurring flu virus infection peps up the antibody response against that first virus.
So, decades after the 1918 epidemic, specific-antibody tests were performed on elderly people born at that time to determine what kind of virus had infected them in those years. It turned out to be what we now call H1N1 virus.
Flu viruses are viruses with eight RNA strings coding for ten proteins. Two proteins cover the virus surface in a mosaic distribution. The rest rattle around loose, inside the virus. The surface genes, H and N, determine the basic nature of the flu virus and are always represented in its name. The H gene codes for hemagglutinin, and the N gene encodes neuraminidase.
Hemagglutinin is the crucial protein that enables the virus to bind to the cell surface. It thus determines the species specificity of a particular flu virus: which cell in which animal the virus will infect. This is because binding, entry and infection all depend on there being a cell receptor that hemagglutinin happens to fit, like a key in a lock. The receptor is not there to admit a virus; it has some beneficial purpose for the host—but the virus happens to be able to use it. Cell receptors are like the cat-door that lets your pet in and out of the house: they can also let in a much less welcome creature.
Neuraminidase is an enzyme, as indicated by its -ase ending. Like all enzymes, its job it is to eat things. That is, it digests or dissolves certain (p.20) substances, and this can have a constructive or destructive effect. In the flu virus, it is constructive for the virus but destructive for the host cell. As new virus particles are produced inside a cell, they are chemically attracted to the cell wall. They line up there, nudging against the wall, and their neuraminidase munches right through it. This destroys the cell and releases the virus particles to spread in the body.
After H1N1 of 1918, there was H2N1, H2N2, and so on. The genes inside the flu virus make proteins crucial to its virulence. Some act directly, by causing a symptom; some act indirectly, by impeding the host's defense mechanisms. Because the genes inside the flu virus are loose, they can exchange bits within one gene, called recombination, or they can rearrange the eight RNA strings of the flu virus. For example, a hog virus can provide a gene, a chicken or a goose virus another gene, and a human virus a couple of others. This is why new flu viruses keep coming, always with new characteristics. Whatever the combination is in a given year will determine the virulence of the virus, how easily it is transmitted within a species; how easily it attaches itself to a host cell, and how easily it avoids being recognized by the immune system.
To trace the history of H1N1, its genetic code had to be deciphered. The necessary techniques were not available until the last two decades. Then RNA had to be found from an actual flu virus that had infected someone in 1918. Success eventually came to Jeffrey Taubenberger of the Armed Forces Institute of Pathology in Washington, D.C. In the archives of this institute, material was stored from 74 victims of the 1918 flu epidemic. Of these, two samples were suitable for study and found to be positive for influenza RNA. Meanwhile, Johan Hultin obtained tissue from a woman who had been buried in a mass grave of 1918 flu victims in Alaska. This woman's lungs were still in very good condition some eighty years later, because she had been buried in permafrost.
Study of these three persons confirmed the H1 identity of the 1918 hemagglutinin gene. This H gene clearly belonged to the group of genes from viruses that have caused epidemics in people over the decades since 1918. However, the one virus whose H gene resembled it most was a hog virus isolated in 1930. This confirms the view that, after humans contracted the 1918 flu virus, we subsequently infected pigs.
The genealogical tree of flu viruses has two main branches, one with all the bird viruses and one with swine and human viruses. If avian flu viruses, and thus birds, were the source of the flu viruses now adapted to humans and pigs, the genealogical tree showed that the avian precursor (p.21) of the 1918 virus infected its first human about 1905. We now know that of all the flu viruses ever found in people, the 1918 virus is the most like a bird virus.
Researchers had long assumed that the exchanging and re-arranging of the eight loose RNA fragments in the virus particle determined the character of each flu virus. Mark and Adrian Gibbs, a father and son team from Australia, very recently came up with a revolutionary idea for explaining the aggressiveness of the 1918 virus. They envision that, in addition to the exchange of whole genes, there is formation of entirely new genes; this is done by pasting parts of a gene together rather than swapping an entire gene, and it can happen not only with the internal flu genes but with H and N on the surface.
There is really only one way in which all this could take place: recombination. This happens when a host is invaded by two virus populations—for example, avian flu virus and human flu virus. One virus from each population penetrates the same cell, which is possible if they arrive at the receptor at the same instant. Simultaneous infection sounds improbable but is not so unlikely, with millions of viruses jostling for millions of cells.
Once inside the cell, the two different viruses simultaneously reproduce, exchanging bits of genes, and ultimately there is a new virus. It may be a weakling; it may be a dud that does not even survive; but it may be a super flu virus, fitter and perhaps more lethal to people than its forebears.
The Gibbs team suggests that in the 1918 virus, a part of the H gene was from a swine flu virus and another part from a human virus. Assuming that a bird virus managed to infect both people and pigs in about 1905, the result would have been an H1N1 hog virus and an H1N1 human virus. Since a similar flu appeared in army barracks in 1916–17, someone already infected with the human virus must have become infected with the hog virus, combining the two viruses and creating the 1918 virus.
The human-swine flu combination somehow formed the basis of the lethal character of the 1918 virus. It also made the virus better able to spread than any other flu virus. It was no longer limited to one species. Thus, while causing the 1918 epidemic, it also infected pigs and caused a swine flu epidemic. At some point it entered a pig already infected with a true hog flu virus, and from this marriage came the H1N1/Iowa 1930 virus. This virus, isolated from an epidemic in Iowa, has long been known to resemble closely the 1918 human flu virus. It still thrives, having crowded out all other hog flu viruses. The human virus that caused (p.22) the 1918 epidemic has not thrived. It became extinct in man after the 1918 epidemic.
The Gibbs scenario is not implausible. Since 1918, history has brought us more and more evidence for the exchange of influenza viruses among birds, pigs and humans. It seems that bird viruses end up in people, via pigs, each time there is a serious pandemic. This happened in both 1957 and 1968. The explanation lies not only in the genetic composition of these flu viruses but in the receptors on the cells in these three species. Although the 1957 and 1968 flu viruses were in part bird flu viruses, they were not entirely bird viruses—and that was the secret of their success. If they had been bird viruses, they could not have entered human cells. Our cells lack the NeuAc-2,3Gal receptor, which is essential for allowing our infection by avian flu viruses.
Swine, on the other hand, have this receptor for bird flu viruses. Not only that, they have the 2,6Gal receptor for human flu viruses. So pigs can become infected with both avian and human flu viruses. And we know that hog flu viruses can infect people. In 1976, this became painfully obvious once more, when it was feared that an epidemic due to a swine virus would erupt among military recruits in America. On the basis of this fear, 40 million Americans and a considerably smaller number of Europeans, specifically in The Netherlands, were inoculated against hog flu. But it was a false alarm: no epidemic took place.
True hog flu viruses, as well as avian and human viruses, continue to exist among pigs in various countries, specifically in Europe and Asia. In the 1970s, H3N2 viruses were transmitted from humans to pigs in Europe. Over the next two decades, a bird virus of the H1N1 type was endemic among pigs in Europe. So nobody was much surprised when, in the mid-1980s, pigs in Italy were found to have viruses which looked like human H3N2 on the outside and like bird or hog H1N1 on the inside. These avian-human reassortant viruses caused flu on a limited scale among Europeans during the next few years. They spread among pigs in China and emerged as the flu virus of a child in Hong Kong, who was infected in 1999.
The story becomes even more complicated. Chinese pigs were found to be infected in large numbers with this H3N2 virus and also very often with a second virus, H9N2, which had originated in birds, probably ducks. The latter virus was widespread among all kinds of fowl in the markets of South China, specifically in Hong Kong. It also was able to cause flu in people, as was found in 1998 in Guangdong and in 1999 in (p.23) Hong Kong. Fortunately, none of these H9N2 infections was serious and all victims recovered quickly.
In 1997, however, a virus had emerged in Hong Kong that looked much more ominous than any other influenza virus. It was an avian virus, H5N1, which not only infected birds but made them very sick. Of all the chickens infected, 70 to 100 percent died.
It also made people sick and of 18 infected, 6 died. The virus seemed to be transmitted directly from chickens to people. This was very bad news, but luckily it could not spread person to person; each human case resulted from exposure to a chicken. The disease struck persons between 1 and 60 years of age. It seemed to bypass the elderly, perhaps because they seldom bought fowl in the markets. But among adults up to 60, the risk of death increased with age. The first person to die from the H5N1 bird virus was a 3-year-old boy, but other deaths were a girl of 13, a young woman of 25, a man of 54, and a man of 60. Further disaster could be prevented only by slaughtering millions of chickens at thousands of poultry farms and markets in the Hong Kong vicinity.
The 1997 virus had a short run, but it seemed to be even more dangerous to humans than the 1918 virus. Was it now possible for some avian viruses to infect humans directly, without first making a stop in pigs? And if so, were these bird flu viruses more lethal than any other flu virus seen by man?
Some 30 years before that, the 1968 epidemic of Hong Kong flu had featured an H3N2 with a totally new H gene. The epidemic of 1957 was caused by an H2N2 virus with a new H gene and a new N gene. In both cases, as in 1918, avian viruses were able to infect humans after gaining genes or parts of genes from flu viruses of pigs or humans. But the Hong Kong virus of 1997 seemed to be entirely a bird virus.
A new phase seems to have begun in the evolution of avian flu viruses. They have found their way directly to man. The H5N1 of 1997 that had killed chickens in great numbers around Hong Kong was identical to the virus that infected 18 people—except for one amino acid. A change in this one bit of one protein, near the spot where viral hemagglutinin attaches to the host cell, was apparently enough to make a true bird virus spread easily to people. If the virus could not spread among people, that was probably because it needed direct contact; it was not sufficiently infectious when spread by aerosol particles.
How do we know the H5N1 virus could not spread person to person? Because each of the 18 persons was infected by a distinct strain of H5N1. (p.24) So several infections from different sources had occurred. Direct contact between chickens and people was needed. The final proof of this came when all chickens in Hong Kong were slaughtered. Immediately there were no more H5N1 infections in people. The danger of an epidemic had passed, despite the fact that not one human being was immune to this virus.
The great aggressiveness of the H5N1 virus was based on its H gene, on the one hand, and on an internal gene, on the other. As early as the 1970s, this virus was known in Chinese ducks and geese. The H5 gene seems to have originated with the geese. The source of the N gene is still unknown, but the eight internal proteins seem to have come from a quail virus of the H9N2 type.
The H5 gene has been stable over the years in all its avian hosts, which suggests that it is very well adapted to geese and even to chickens. However, the internal genes of H5N1 viruses are highly subject to change, which suggests that they are still adapting to chickens. Wild birds, such as ducks and geese, seem to be the true pools in which this and other avian flu viruses thrive. Domestic animals such as chickens only function as a leg up to man, as is the case with pigs. Ordinarily, a duck or goose virus cannot be transmitted to man, but a hog or chicken virus can. The flu virus spreads death and destruction among these new intermediate hosts but still causes no disease in wild ducks and geese.
Does the flu virus derive some benefit from making a trip, on a somewhat regular basis, from wild water fowl to domestic animals and from those animals to man? Or is the trip only an accidental event without any meaning for the survival of avian flu viruses in general?
We do not know. But we do know that the flu viruses of ducks and geese evolve very slowly. The influenza virus feels at home with these water fowl which live in the wild, and it no longer needs to adapt to them. After a trip to chickens, horses or people, could these viruses return to ducks and geese as new strains? Might such strains even make them sick? Do duck and geese flu strains ever become extinct? All these things seem unlikely because their well-adapted viruses are so stable.
Meanwhile, new flu virus families have formed, based on avian or part-avian ancestors. They have settled permanently in pigs, horses and other mammals since the beginning of the 20th century. The diversity in species of flu viruses has increased, because the number of infected species has increased. At this point we could never wipe influenza viruses off the face of the earth. They are able to spread rapidly, they can move (p.25) across the barriers between species, and they no longer have just one or two pools (e.g., ducks and geese).
The flu virus has ensured eternal life for itself as a virus by jumping from one host to another. More and more flu variants have apparently learned how to do this trick, and not only in China. In 2002–2003, chicken farms in the Netherlands were struck by the avian flu strain H7N7, and soon more than 100 humans had been infected. The chicken virus H7N7 had the unique and dangerous ability to jump from human to human. A Dutch veterinarian died and, by ominous coincidence, H5N1 claimed one more Chinese victim in the same year.
The H7N7 infection soon showed up at some Dutch pig farms. In the Netherlands, there are over 10 million pigs and even more chickens; some farms raise both types of animals. As for humans, the country is one of the most densely populated in the world. All ingredients are in place for the next killer flu virus, and this time it may not be from China.