The Great Influenza (16 page)

It is, however, not only an endemic disease, a disease that is always around. It also arrives in epidemic and pandemic form. And pandemics can be more lethal (sometimes much, much more lethal) than endemic disease.

Throughout known history there have been periodic pandemics of influenza, usually several a century. They erupt when a new influenza virus emerges. And the nature of the influenza virus makes it inevitable that new viruses emerge.

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The virus itself is nothing more than a membrane (a sort of envelope) that contains the genome, the eight genes that define what the virus is. It is usually spherical (it can take other shapes), about 1/10,000 of a millimeter in diameter, and it looks something like a dandelion with a forest of two differently shaped protuberances (one roughly like a spike, the other roughly like a tree) jutting out from its surface.

These protuberances provide the virus with its actual mechanism of attack. That attack, and the defensive war the body wages, is typical of how shape and form determine outcomes.

The protuberances akin to spikes are hemagglutinin. When the virus collides with the cell, the hemagglutinin brushes against molecules of sialic acid that jut out from the surface of cells in the respiratory tract.

Hemagglutinin and sialic acid have shapes that fit snugly together, and the hemagglutinin
binds
to the sialic acid 'receptor' like a hand going into a glove. As the virus sits against the cell membrane, more spikes of hemagglutinin bind to more sialic acid receptors; they work like grappling hooks thrown by pirates onto a vessel, lashing it fast. Once this binding holds the virus and cell fast, the virus has achieved its first task: 'adsorption,' adherence to the body of the target cell.

This step marks the beginning of the end for the cell, and the beginning of a successful invasion by the virus.

Soon a pit forms in the cell membrane beneath the virus, and the virus slips through the pit to enter entirely within the cell in a kind of bubble called a 'vesicle.' (If for some reason the influenza virus cannot penetrate the cell membrane, it can detach itself and then bind to another cell that it
can
penetrate. Few other viruses can do this.)

By entering the cell, as opposed to fusing with the cell on the cell membrane (which many other viruses do) the influenza virus hides from the immune system. The body's defenses cannot find it and kill it.

Inside this vesicle, this bubble, shape and form shift and create new possibilities as the hemagglutinin faces a more acidic environment. This acidity makes it cleave in two and refold itself into an entirely different shape. The refolding process somewhat resembles taking a sock off a foot, turning it inside out, and sticking a fist in it. The cell is now doomed.

The newly exposed part of the hemagglutinin interacts with the vesicle, and the membrane of the virus begins to dissolve. Virologists call this the 'uncoating' of the virus and 'fusion' with the cell. Soon the genes of the virus spill into the cell, then penetrate to the cell nucleus, insert themselves into the cell's genome, displace some of the cell's own genes, and begin issuing orders. The cell begins to produce viral proteins instead of its own. Within a few hours these proteins are packaged with new copies of the viral genes.

Meanwhile, the spikes of neuraminidase, the other protuberance that jutted out from the surface of the virus, are performing another function. Electron micrographs show neuraminidase to have a boxlike head extending from a thin stalk, and attached to the head are what look like four identical six-bladed propellers. The neuraminidase breaks up the sialic acid remaining on the cell surface. This destroys the acid's ability to bind to influenza viruses.

This is crucial. Otherwise, when new viruses burst from the cell they could be caught as if on fly paper; they might bind to and be trapped by sialic acid receptors on the dead cell's disintegrating membrane. The neuraminidase guarantees that new viruses can escape to invade other cells. Again, few other viruses do anything similar.

From the time an influenza virus first attaches to a cell to the time the cell bursts generally takes about ten hours, although it can take less time or, more rarely, longer. Then a swarm of between 100,000 and 1 million new influenza viruses escapes the exploded cell.

The word 'swarm' fits in more ways than one.

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Whenever an organism reproduces, its genes try to make exact copies of themselves. But sometimes mistakes (mutations) occur in this process.

This is true whether the genes belong to people, plants, or viruses. The more advanced the organism, however, the more mechanisms exist to prevent mutations. A person mutates at a much slower rate than bacteria, bacteria mutates at a much slower rate than a virus - and a DNA virus mutates at a much slower rate than an RNA virus.

DNA has a kind of built-in proofreading mechanism to cut down on copying mistakes. RNA has no proofreading mechanism whatsoever, no way to protect against mutation. So viruses that use RNA to carry their genetic information mutate much faster (from 10,000 to 1 million times faster) than any DNA virus.

Different RNA viruses mutate at different rates as well. A few mutate so rapidly that virologists consider them not so much a population of copies of the same virus as what they call a 'quasi species' or a 'mutant swarm.'

These mutant swarms contain trillions and trillions of closely related but different viruses. Even the viruses produced from a single cell will include many different versions of themselves, and the swarm as a whole will routinely contain almost every possible permutation of its genetic code.

Most of these mutations interfere with the functioning of the virus and will either destroy the virus outright or destroy its ability to infect. But other mutations, sometimes in a single base, a single letter, in its genetic code will allow the virus to adapt rapidly to a new situation. It is this adaptability that explains why these quasi species, these mutant swarms, can move rapidly back and forth between different environments and also develop extraordinarily rapid drug resistance. As one investigator has observed, the rapid mutation 'confers a certain randomness to the disease processes that accompany RNA [viral] infections.'

Influenza is an RNA virus. So is HIV and the coronavirus. And of all RNA viruses, influenza and HIV are among those that mutate the fastest. The influenza virus mutates so fast that 99 percent of the 100,000 to 1 million new viruses that burst out of a cell in the reproduction process are too defective to infect another cell and reproduce again. But that still leaves between 1,000 and 10,000 viruses that
can
infect another cell.

Both influenza and HIV fit the concept of a quasi species, of a mutant swarm. In both, a drug-resistant mutation can emerge within days. And the influenza virus reproduces rapidly - far faster than HIV. Therefore it adapts rapidly as well, often too rapidly for the immune system to respond.

CHAPTER EIGHT

A
N INFECTION
is an act of violence; it is an invasion, a rape, and the body reacts violently. John Hunter, the great physiologist of the eighteenth century, defined life as the ability to resist putrefaction, resist infection. Even if one disagrees with that definition, resisting putrefaction certainly does define the ability to live.

The body's defender is its immune system, an extraordinarily complex, intricate, and interwoven combination of various kinds of white blood cells, antibodies, enzymes, toxins, and other proteins. The key to the immune system is its ability to distinguish what belongs in the body, 'self,' from what does not belong, 'nonself.' This ability depends, again, upon reading the language of shape and form.

The components of the immune system (white blood cells, enzymes, antibodies, and other elements) circulate throughout the body, penetrating everywhere. When they collide with other cells or proteins or organisms, they interact with and read physical markings and structures just as the influenza virus does when it searches for, finds, and latches on to a cell.

Anything carrying a 'self' marking, the immune system leaves alone. (It does, that is, when the system works properly. 'Autoimmune diseases' such as lupus or multiple sclerosis develop when the immune system attacks its own body.) But if the immune system feels a 'nonself' marking (either foreign invaders or the body's own cells that have become diseased) it responds. In fact, it attacks.

The physical markings that the immune system feels and reads and then binds to are called 'antigens.' The word refers to, very simply, anything that stimulates the immune system to respond.

Some elements of the immune system, such as so-called natural killer cells, will attack anything that bears any nonself-marking, any foreign antigen. This is referred to as 'innate' or 'nonspecific' immunity, and it serves as a first line of defense that counterattacks within hours of infection.

But the bulk of the immune system is far more targeted, far more focused, far more specific. Antibodies, for example, carry thousands of receptors on their surface to recognize and bind to a target antigen. Each one of those thousands of receptors is identical. So antibodies bearing these receptors will recognize and bind
only
to, for example, a virus bearing that antigen. They will not bind to any other invading organism.

One link between the nonspecific and specific immune response is a particular and rare kind of white blood cell called a dendritic cell. Dendritic cells attack bacteria and viruses indiscriminately, engulf them, then 'process' their antigens and 'present' those antigens - in effect they chop up an invading microorganism into pieces and display the antigens like a trophy flag.

The dendritic cells then travel to the spleen or the lymph nodes, where large numbers of other white blood cells concentrate. There these other white blood cells learn to recognize the antigen as a foreign invader and begin the process of producing huge numbers of antibodies and killer white cells that will attack the target antigen and anything attached to the antigen.

The recognition of a foreign antigen also sets off a parallel chain of events as the body releases enzymes. Some of these affect the entire body, for example, raising its temperature and causing fever. Others directly attack and kill the target. Still others serve as chemical messengers, summoning white blood cells to areas of invasion or dilating capillaries so killer cells can exit the bloodstream at the point of attack. Swelling, redness, and fever are all side effects of the release of these chemicals.

All this together is called the 'immune response,' and once the immune system is mobilized it is formidable indeed. But all this takes time. The delay can allow infections to gain a foothold in the body, even to advance in raging cadres that can kill.

In the days before antibiotics, an infection launched a race to the death between the pathogen and the immune system. Sometimes a victim would become desperately ill; then, suddenly and almost miraculously, the fever would break and the victim would recover. This 'resolution by crisis' occurred when the immune system barely won the race, when it counterattacked massively and successfully.

But once the body survives an infection, it gains an advantage. For the immune system epitomizes the saying that that which does not kill you makes you stronger.

After it defeats an infection, specialized white cells (called 'memory T cells') and antibodies that bind to the antigen remain in the body. If any invader carrying the same antigen attacks again, the immune system responds far more quickly than the first time. When the immune system can respond so quickly that a new infection will not even cause symptoms, people become immune to the disease.

Vaccinations expose people to an antigen and mobilize the immune system to respond to that disease. In modern medicine some vaccines contain only the antigen, some contain whole killed pathogens, and some contain living but weakened ones. They all alert the immune system and allow the body to mount an immediate response if anything bearing that antigen invades the body.

The same process occurs in the body naturally with the influenza virus. After people recover from the disease, their immune systems will very quickly target the antigens on the virus that infected them.

But influenza has a way to evade the immune system.

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The chief antigens of the influenza virus are the hemagglutinin and neuraminidase protruding from its surface. But of all the parts of the influenza virus that mutate, the hemagglutinin and neuraminidase mutate the fastest. This makes it impossible for the immune system to keep pace.

By no means do the antigens of all viruses, even all RNA viruses, mutate rapidly. Measles is an RNA virus and mutates at roughly the same rate as influenza. Yet measles antigens do not change. Other parts of the virus do, but the antigens remain constant. (The most likely reason is that the part of the measles virus that the immune system recognizes as an antigen plays an integral role in the function of the virus itself. If it changes shape, the virus cannot survive.) So a single exposure to measles usually gives lifetime immunity.

Hemagglutinin and neuraminidase, however, can shift into different forms and still function. The result: their mutations allow them to evade the immune system but do not destroy the virus. In fact, they mutate so rapidly that even during a single epidemic both the hemagglutinin and neuraminidase often change.

Sometimes the mutations cause changes so minor that the immune system can still recognize them, bind to them, and easily overcome a second infection from the same virus.

But sometimes mutations change the shape of the hemagglutinin or neuraminidase enough that the immune system can't read them. The antibodies that bound perfectly to the old shapes do not fit well to the new one.

This phenomenon happens so often it has a name: 'antigen drift.'

When antigen drift occurs, the virus can gain a foothold even in people whose immune system has loaded itself with antibodies that bind to the older shapes. Obviously, the greater the change, the less efficiently the immune system can respond.