Parasite Rex

3 The Thirty Years’ War

A man came one day to the Royal Perth Hospital in Australia saying he was tired. He had been tired for two years, and now, in the summer of 1980, he decided it was time to find out what was wrong with him. His health wasn’t perfect, but it wasn’t terrible either. He had been a heavy smoker in his teens and twenties, but at forty-four, his only indulgence was a glass of white wine each night.

His doctor could feel through his skin that his liver was swollen. On an ultrasound image, two of its three lobes loomed too large. Yet, there were no signs of the kinds of trouble the doctor would expect to find, such as a tumor or cirrhosis. It was when the doctor got the report on the man’s stool that he realized what had happened: the stool was loaded with the spiny eggs of Schistosoma mansoni—blood flukes found only in Africa and Latin America.

The doctor had the man walk him through his life. It had started roughly. He had been born in Poland in 1936. The Soviet army had taken his family during the Second World War and held them in a Siberian prison camp. Toward the end of the war they had escaped, traveling through Afghanistan and Persia, finally ending up in a refugee camp in East Africa. For six years, savannas were his playgrounds, until 1950, when his family emigrated to Australia. He had remained there for the rest of his life.

The math is simple enough, yet hard to believe: the only time in the man’s life when he was anywhere near Schistosoma mansoni was in the late 1940s. When he swam and bathed in Tanzanian lakes, at least one pair of flukes had invaded his skin and journeyed into his veins; they had traveled with him to Australia and started a new life with him, and male and female flukes had gone on living, quietly entwined and pumping out eggs, for over thirty years.

What makes the longevity of the blood flukes all the more impressive is that they attained it under perpetual menace and attack. Lankester was under the impression that once inside a host, a parasite was home free. It needed to do nothing more than drink up the food that bathed it, and could in fact do nothing more. But he wrote his essay “Degeneration” in 1879, when immunology, the science of the body’s defenses, was still little better than alchemy. Physicians knew that they could protect people from smallpox by injecting a bit of a pox sore into them, but they had no idea how they were actually saving lives. Within a few years of Lankester’s essay, scientists would discover predatory cells roving our bodies and devouring bacteria, and immunology was born.

To sum up what scientists have learned since then about the immune system is like trying to reproduce the Sistine Chapel in crayon. It is orchestral in its complexity, with a huge diversity of cells, all communicating among each other with a dictionary’s worth of signals, along with dozens of kinds of molecules designed to help the cells decide what should be destroyed and what should be spared. It acts like a blood-borne brain. But here, at any rate, is a brief survey of the most important ways in which our bodies kill parasites.

The immune system attacks an intruder—bacteria crawling into a cut, for instance—in a succession of waves. One of the first waves is a collection of molecules called complement. When complement molecules hit the surface of bacteria, they latch on and change their shape so that they can snag other passing complement molecules. Gradually the molecules build up on the surface. They assemble themselves into tools of destruction, like drills that can open a hole in the bacteria’s membranes. They also act like beacons, making the bacteria more visible to immune cells. Complement molecules also land on our own cells, but they do no harm. Our cells are coated with molecules that can clamp onto a complement molecule and cut it apart.

Also arriving early at the cut are wandering immune cells, the most important of which are the macrophages. They have some crude ways of recognizing bacteria if they happen to bump into them, and they can suck the invaders into their cores and slowly digest them. At the same time, the macrophages also release signals that bring the rest of the immune system’s attention to the site. Some of these signals make the infection swell up by loosening the neighboring blood vessel walls. That lets other immune cells and molecules flood into the tissue. The signaling molecules released by the macrophages also latch onto immune cells that happen to be flowing by in nearby blood vessels. They lead the cells through the vessel wall and to the infection, like a boy dragging his mother by the hand down a toy store aisle.

With enough time, the immune system can organize a new wave of attack, using much more sophisticated cells: B and T cells. Most of our cells come with a standard issue of receptors on their surface. One red blood cell looks pretty much like the next. But when B and T cells form, they shuffle the genes that make the receptors on their surface. The cells use the altered genes to build new receptors with shapes not found in any other immune cell. This shuffling can produce hundreds of billions of different shapes, so that each new B or T cell is as distinct as a human face.

Because they are so diverse, B and T cells can grab a huge range of molecules, including the ones on the surface of invaders. (Foreign molecules that trigger an immune response are called antigens.) First, though, the cells have to get a proper introduction to the antigens. This job is accomplished by macrophages and other immune cells. As they engulf bacteria or their cast-off fragments the immune cells cut them up into little pieces. They then bring these antigens to their surface, displaying them in a special cup (the major histocompatibility complex, or MHC for short). Parading these conquests, the immune cells travel into the lymph nodes. There they bump into T cells. If a T cell has the right kind of receptor, it can lock onto the antigens displayed by a macrophage. As soon as it recognizes the antigen, the T cells start multiplying quickly into a battalion of identical cells, all equipped with the same receptor.

These T cells can take one of three forms, each of which kills the invaders in a different style. Sometimes they become killer T cells, which search the body for cells that have been invaded by pathogens. They recognize infected cells, thanks again to MHC. Like macrophages, most cells in the human body can display antigens on MHC receptors of their own. If the killer T cell recognizes these signs of trouble, it commands an infected cell to commit suicide. The parasite within dies along with it.

In other cases, activated T cells set out to coordinate other immune cells to do a better job of killing. Sometimes they help by becoming inflammatory T cells. These cells crawl their way to the macrophages that are struggling to fight the rising tide of bacteria. They lock onto the antigen displayed on the macrophage’s MHC. That locking acts like a trigger, turning the macrophage into a more violent killer, spraying more poisons. At the same time, the inflammatory T cells help make the cut swell far more than the macrophages can manage on their own. The inflammatory T cells also kill off tired old macrophages and spur the production of new ones to devour their elder cousins. They’re like battle-hungry generals: they’re good to have around in a war but can’t be allowed to get out of control. Too much inflammation, too many poisons created by macrophages, and the immune system will start destroying the body itself.

In the third form that T cells take, they help B cells make antibodies. B cells have the same diversity of surface molecules as T cells, so they also have the potential to snag onto billions of different kinds of antigens. After a B cell has latched onto a fragment, a helper T cell may come along and hook onto it at the same time. In these unions, the T cell can give the B cell signals to start making antibodies. Antibodies are a kind of free-floating version of a B cell receptor, also able to clasp onto an antigen from an invader.

Once they’re activated, B cells spew antibodies out into the body, and depending on the particular antibody, they can fight the infection in several ways. They can cluster around a toxin made by bacteria and neutralize it. They can help the complement molecules trying to drill into the bacteria to make bigger holes. They can latch onto bacteria and foul up the chemistry they use to invade the body’s cells. They can tag bacteria to make them a clearer target for macrophages.

As the majority of B and T cells go about eradicating the bacteria from the cut, a few sit out the attack. These are known as memory cells; it is their job to preserve a record of the invader for many years after the infection. If the same kind of bacteria should get into the body again, the memory cells can switch back on and orchestrate a swift, overwhelming assault. These cells are the secret to vaccines. Even if immune cells are exposed only to an antigen, they can produce memory cells. Because a vaccine contains only a molecule and not a living organism, it doesn’t make a person sick, but it can still prime the immune system to wipe out the pathogen if it ever meets up with it again.

T cells, B cells, macrophages, complement molecules, antibodies, and all the other parts of the immune system form a tight net that perpetually sweeps our bodies clean. Every now and then, though, a parasite slips through and establishes itself. Its success isn’t simply due to some oversight but to the parasite’s ability to escape the immune system. Bacteria and viruses have their own tricks, but many of the most intriguing strategies are found among the “classic” parasites—the protozoa, flukes, tapeworms, and other eukaryotes. They can evade the immune system, distract it, wear it out, and even take control of it, confusing its signals into a weakened state or, if need be, a heightened one. One sign of the sophistication of these parasites is the fact that there is still no vaccine for them, while there are many vaccines for viruses and bacteria. If Lankester had known any of this, perhaps he wouldn’t have given parasites the bad reputation they still haven’t been able to shake.

In September 1909, a strong young man from Northumberland came down with sleeping sickness in northeastern Rhodesia, near the Luangwa River. His illness wasn’t diagnosed for two months, but soon afterward he arrived back in England, and was treated by doctors at the Liverpool School of Tropical Medicine. He was admitted to the Royal Southern Hospital on December 4, where his doctor was Major Ronald Ross. Ross was one of the giants of tropical medicine, who a decade earlier had figured out the cycle of malaria: the way Plasmodium travels between mosquito and human. The sleeping sickness patient’s blood was seething with the trypanosome parasites, thousands of augur-shaped creatures to every drop. His glands swelled, and his legs became covered in rashes. For weeks he dwindled. Ross tried to destroy the parasites with an arsenic compound but had to stop when it damaged the man’s eyes instead. In April, the patient vomited for four days and lost ten pounds. From then on, he became drowsier and drowsier, although he would occasionally perk up. His liver expanded, and the vessels in his brain became congested.

Ross began trying out other treatments. He inoculated a rat with the blood from his patient, let the parasites multiply, and then drew off some of the rat’s blood. He heated it to kill the trypanosomes, and then injected this crude vaccine back into the man. It did nothing. In May, his patient’s anal sphincter became paralyzed and Ross was sure he was going to die, but a week later he went through a sudden remarkable improvement. It lasted only a few days before he faded again, came down with pneumonia, and passed away. At the autopsy, Ross couldn’t find a single trypanosome.

A few years earlier, Ross had invented a quick way to detect blood parasites, and he used the method on the patient during his final three months. In the process he got the world’s first day-by-day portrait of sleeping sickness. He plotted it out on what he described in a report on his patient as a “remarkable graph.” The graph showed a clear rhythm: for a few days the trypanosomes would skyrocket, multiplying by as much as fifteen-fold. Then, just as suddenly, they would drop back down to barely detectable numbers. The cycle would take a week or so, and the man’s fevers and changing white blood cell counts followed in its wake. The man hadn’t been attacked by a single assault of parasites—a string of outbreaks had flared and died within him.

Ross saw in his patient “a struggle between the defensive powers of the infected body and the aggressive powers of the trypanosomes.” Exactly what the nature of that struggle was he couldn’t say. With another ninety years of study, scientists still can’t make a sleeping sickness vaccine, but they do at least understand how trypanosomes ride their spiky wave until their host dies. They play an exhausting game of bait-and-switch.

If you could fly Fantastic Voyage–style over a trypanosome, you’d be bored with the view. It would be like the drabbest cornfield in Iowa: millions of stalks all crammed together with barely a space between them. Fly to the next trypanosome and there’s no relief: the cornstalks would be identical with the first one. In fact, go to any of the millions upon millions of trypanosomes in a human host at any given moment, and you’ll most likely find the same coat.

For a human immune system, these parasites should be as easy to kill as fish in a barrel. If the immune system learns how to recognize only one of these cornstalk molecules, it can attack just about every parasite in the body. And indeed, as a host’s B cells begin to produce antibodies tailored to the cornstalks, the trypanosomes start to die. But not completely. Just when it looks as though the trypanosomes are about to disappear into obscurity, their numbers bottom out and rise again. The view has changed. If you were now to fly over the trypanosomes, you’d find not corn but wheat—an utterly drab expanse, but a completely different kind of expanse.

The quick change happens thanks to the unique way the trypanosome’s genes are laid out. The instructions for building the molecule that makes up the trypanosome’s coat sit on a single gene. Normally, when the trypanosome divides, the new parasites use that same gene to make the same coat. But once every ten thousand divisions or so, a trypanosome will abruptly retire the gene, cutting it out of its position in the parasite’s DNA. It then reaches into a reserve of a thousand other coat-building genes, selects one, and pastes it into the old gene’s position. The new gene starts making its surface molecule: a molecule that’s similar to the previous one, but not identical with it.

Now the immune system, so focused on the first coat, needs time to recognize the second one and make new antibodies for it. In that time, the trypanosomes with the new coat are safe, and they can multiply furiously. By the time the immune system catches up and is attacking the trypanosomes with a new antibody, another trypanosome has installed a third gene and is making a third coat. The chase goes on for months or years, the trypanosomes flinging off their coats and putting on new ones hundreds of times. With so many different kinds of trypanosome fragments building up in the bloodstream, the host’s immune system becomes chronically overstimulated, attacking its own body until the victim dies.

This bait-and-switch strategy works only because the parasite can dip into a reservoir of coat-producing genes. But these genes can’t be called from their bullpen in any random order. Say that the first generation of trypanosomes to get into a person’s body were to switch on all their coat-building genes. The immune system would make antibodies to all of them and bring the infection to a quick stop. And if a new generation of parasites were to turn back to an old coat gene, the immune system would still have some antibodies left over with which it could fight it. Instead, the trypanosomes carefully go through their lineup in a predetermined order. Take two trypanosome clones and infect two mice with them, and their descendants will switch on the same genes in the same order. That way, the parasite can stretch out its infection for months.

Ronald Ross is remembered today for his work on malaria rather than sleeping sickness. Yet he never managed to discover much about the way Plasmodium fights the human immune system. Trypanosomes flaunt their evasions through their booms and busts, but Plasmodium is subtler. For much of its time in the body, the parasite runs from one cover to the next. When it firsts enters a human through a mosquito bite, it can get to the liver in half an hour, which is often fast enough to escape the notice of the immune system. The parasite slides into a liver cell to mature, and here it comes to the body’s attention. The liver cells grab stray proteins from Plasmodium floating inside them, cut them up, and shuttle them up to their surfaces, where they display them on their MHC molecules. The host’s immune system recognizes these antigens and starts organizing an attack against the sick liver cells. But the attack takes time—enough time for the parasite to divide into forty thousand copies in a week, burst out of the liver, and seek out blood cells. By the time the immune system is ready to destroy infected liver cells, the cells have become empty husks.

Meanwhile, the parasites are invading red blood cells and making their home improvements. Plasmodium has to go to a lot of effort to make up for the cells’ lack of genes and proteins, but their barrenness has its advantages as well: a red blood cell is a good place to hide. Because they don’t have genes, they can’t make any MHC molecules, so they have no way of showing the immune system what’s inside them. For a time, Plasmodium can enjoy perfect camouflage inside the cell.

As the parasite divides and fills the cell it has to start supporting the membrane with its own proteins. To avoid being destroyed in the spleen, it builds knobs on the surface of the cell, each with little latches that can snag onto the walls of blood vessels. These latches pose a danger of their own: they risk getting the attention of the immune system. Antibodies can be made against them, and an army of killer T cells can be assembled that recognizes these signs of an infected cell.

Because these latches can be recognized by the immune system, scientists have spent a lot of time studying them in the hope of building a vaccine against malaria. In the 1990s they were able for the first time to sequence the genes that carry the instructions for the latches. They found that it takes only a single gene to make a latch, but there are over a hundred different genes in Plasmodium DNA that can make one. And while every sort of latch can hook the red blood cell to a blood vessel wall, each one has a unique shape.

When Plasmodium first invades a red blood cell, it switches on many of these latch-making genes at once, but the parasite selects only one kind of latch to put on its surface. The red blood cell thus will be covered with that particular style of latch alone. When the cell ruptures, sixteen new parasites emerge and they will almost always use the same gene to make the same latch. But every now and then, a parasite will switch to another gene and make new latches that are unrecognizable to the immune system. And that’s how Plasmodium manages to hide in plain sight: by the time the immune system has recognized its latches, the parasite is making new ones. In other words, malaria uses a bait-and-switch strategy very much like the one used by sleeping sickness. Although Ronald Ross didn’t know it, his patients struggling against sleeping sickness and malaria were losing to the same exhausting game.

Plasmodium is only one of many parasites that live inside our cells. Some can live in any kind of cell, while others choose only one. Some even specialize in the most dangerous cells of all, the macrophages whose job it is to kill and devour parasites. In this last category is the protozoan Leishmania. There are a dozen species of this parasite all of which are carried from person to person by biting insects called sand flies. Each species causes a disease of its own. Leishmania major causes Oriental sore—an annoying blister that heals itself like a canker. Leishmania donovani attacks the macrophages inside the body and can kill its host within a year. And a third Leishmania parasite, Leishmania brasiliensis, causes espundia, in which the parasite chews away at the soft tissue of the head until its victim is faceless.

Leishmania doesn’t have to muscle its way into its host macrophage the way Plasmodium pushes into red blood cells. It’s more like an enemy spy that knocks at the door of police headquarters and asks to be arrested. When the parasite is injected during a sand fly’s bite, it attracts complement molecules that try to drill into its membrane and attract macrophages to devour it. Leishmania can stop complement from drilling into it, but it doesn’t destroy the molecule. It still lets complement do its other job: to act like a beacon. A macrophage crawls over the parasite, detects the complement, and opens a hole in its membrane to engulf Leishmania.

The macrophage swallows up the parasite in a bubble that sinks into its interior. Normally, this would become a death chamber for a parasite. The macrophage would fuse that bubble with another one filled with molecular scalpels, which it would use to dismantle Leishmania. But somehow—scientists still don’t know how—Leishmania stops the bubbles from fusing. Its own bubble, now safe from attack, becomes a comfortable home where the parasite can thrive.

Leishmania not only alters the particular macrophage it’s inside but changes the body’s entire immune system. When young T cells encounter antigens for the first time and lock onto them, they can become helper T cells. Which type of helper they become—the inflammatory kind or the kind that helps B cells make antibodies—depends on the balance of certain signals floating through the body. At first, both kinds of T cells start to multiply, but as they do they interfere with one another. In many infections, this struggle tips the balance in favor of one kind of T cell or the other. The winning side launches its own kind of war against the parasite.

Leishmania has figured out how to fix this fight. Clearly, the best way to destroy this parasite would be to make lots of inflammatory T cells. These cells could help the macrophage kill parasites they have swallowed. And that seems, in fact, to be what happens inside people who manage to fight off Leishmania. Parasitologists have run experiments in which they infected mice with Leishmania and siphoned off the inflammatory T cells made by the mice who survived the disease. The parasitologists then injected these T cells into mice that had been genetically stripped of most of their immune system. The injection let the helpless mice fight off the parasite as well.

But often our bodies can’t raise the right defense, and that failure seems to be Leishmania’s doing. Sitting inside its host macrophage, it forces the cell to release the signals that tip the immune system in favor of the T cells that help make antibodies. Since Leishmania is safely hidden inside macrophages, the antibodies can’t reach them. And so the disease goes unchecked.

Plasmodium and Leishmania are fussy about where they live, able to survive only in certain types of cells. Most parasitic protozoa are equally choosy, but there are a few that can invade just about anything. One such species is Toxoplasma gondii, a creature that lives in undeserved obscurity. Few people know about Toxoplasma, even though there’s a fair chance that they are carrying it by the thousands in their brains. A third of all the people in the world are infected by it; in parts of Europe almost everyone is a host.

Although billions of humans carry Toxoplasma, we are not actually the parasite’s natural host. Normally it cycles between cats, domestic and wild, and the animals they eat. The cat releases Toxoplasma’s egg-like oocysts in its feces, and the oocysts can wait in the ground for many years to be picked up by an animal such as a bird, a rat, or a gazelle. In their new host, the oocysts hatch and the protozoa move through the body and look for a cell to make their home.

Toxoplasma is a close relative of Plasmodium, the protozoan that causes malaria, and it also is equipped with the same special machinery around its tip that blasts its way into a cell. But while Plasmodium can live only in liver cells and then red blood cells, Toxoplasma doesn’t much care. It muscles its way into just about any type of cell.

Once Toxoplasma has invaded a cell, it starts feeding and reproducing. After it has divided into 128 new copies, it tears the cell open, and the new parasites spill out, ready to invade fresh cells. After a few days, the parasite shifts gears. Now, instead of invading cells, it builds shells, each of which hides a few hundred Toxoplasma individuals. Every now and then, one of the cysts will break open and the parasites inside will invade cells and produce new Toxoplasma. But their descendants promptly build cysts of their own and vanish into them. There they will sit for years, until their host is eaten by a cat. Once inside their final host, they wake up again. They start dividing. Male and female sexual forms are born. They mate and make oocysts, and the cycle starts over again.

If a person should swallow Toxoplasma eggs, either in a speck of soil or in the meat of an infected animal, the parasite will go through this same fast-then-slow progression. Humans hardly know what’s happening during a Toxoplasma invasion; at worst it feels like a light flu. Once the parasite has retreated to its quiet cyst, a healthy person doesn’t notice it at all. It might seem as if Toxoplasma, in all its meekness, doesn’t warrant mention alongside parasites like trypanosomes and Plasmodium. But Toxoplasma actually manipulates the immune system of its host as elegantly as these other species do. If the parasite were to multiply madly, grinding up every cell in its host’s body, it would find itself inside a corpse rather than a living host. That would hardly be the sort of thing that a cat would want to hunt. Toxoplasma wants to keep its intermediate host alive, so it uses its host’s immune system to hold itself in check.

Toxoplasma does this with the exact opposite strategy as Leishmania. Leishmania pushes the immune system to make the T cells that help make antibodies. But Toxoplasma releases a molecule that tips the balance in favor of the inflammatory T cells. The inflammatory T cells rise up in huge numbers, turning macrophages into Toxoplasma assassins, hunting down the protozoa and blasting them apart. Only Toxoplasma that have hunkered down inside tough-walled cysts can survive the attack. From time to time, a few parasites break out of their cysts, squirting a fresh supply of their stimulating molecules, which reenergize the immune system like a booster vaccine. Roused again, the host’s macrophages drive the parasites back into their cysts. And so, thanks to Toxoplasma’s manipulations, its host stays healthy and able to fight disease while the parasite sits comfortably in its cyst, waiting to reach the promised land of a cat’s insides.

Toxoplasma becomes a threat to humans only when the cozy arrangement it creates falls apart. A fetus, for example, doesn’t have an immune system of its own. It is protected only by antibodies made by its mother that cross the placenta. The mother’s T cells are forbidden from crossing into the fetus, because they would act as if the fetus were a gigantic parasite and would kill it. Maternal antibodies do a good job against a flu virus or Escherichia coli bacteria, but they can’t protect against Toxoplasma. For that, the fetus would need inflammatory T cells to drive them into their cysts. As a result, it’s very dangerous for a woman to get a Toxoplasma infection during pregnancy. If the parasite manages to pass from her into her fetus, it will reproduce wildly. It will try to make the immune system rein it in, but inside the fetus there’s no audience to hear its calls. It simply proliferates until it causes massive, often fatal, brain damage.

In the 1980s, Toxoplasma became an accidental killer of another sort of human host: people suffering from AIDS. Human immunodeficiency virus, or HIV, the cause of AIDS, invades inflammatory T cells, using them to reproduce and killing them in the process. When Toxoplasma in a person with AIDS pops out of its cyst and divides, it expects a strong immune response to drive it back into hiding. But with hardly any inflammatory T cells left, its host is as helpless as a fetus. The parasite multiplies madly, causing much of its damage in the brain. Its host goes into a delirium and sometimes dies.

For over a decade, doctors could do almost nothing to stop the rampage of Toxoplasma in AIDS victims. But in the 1990s, scientists developed drugs that for the first time could slow down the replication of HIV and bring back the inflammatory T cells. In the relative few who can afford these drugs, Toxoplasma has gone gladly back into its lair, driven there by a healthy squad of T cells. But the millions who can’t afford these drugs continue to face madness brought on by this reluctant parasite.

Surviving the immune system is certainly difficult for a single-celled parasite, but at least it has the advantage of size. It can hide in the pockets of cells or the crooks of lymphatic ducts. The same can’t be said for parasitic animals. These multicellular creatures cross the radar of the immune system like vast dirigibles. They are as obvious as a transplanted lung. And without a continual supply of immune-suppressing drugs to hold off the immune system, a transplanted lung will die under its attack. Yet, parasitic animals, some sixty feet long, can live for years inside our bodies, feasting and breeding hundreds of thousands of young.

They thrive because they have many more ways of fooling our immune systems. One remarkable example is the tapeworm Taenia solium. Before the eggs of Taenia can turn into long ribbons in our bodies, they first need to spend some time in an intermediate host, usually a pig. The pig swallows the eggs with its food, and parasites hatch once they get to the intestines. They use enzymes to dig a hole in the intestines and wriggle their way out. Once they reach a capillary, they ride the bloodstream through the body to a muscle or an organ. There they disembark and settle down, growing into pearly marbles. They can wait for their final host in these cysts for years.

If pigs were the only places where tapeworms spent their cyst years, we’d probably know nothing about how they survive the immune system. But sometimes the eggs of Taenia solium end up in humans. (A person with a full-grown tapeworm inside him may get eggs on his hands and then make food for other people, for example.) The eggs proceed to act as if they’re in a pig: they hatch, and the larvae go through the same steps of breaking out of the intestines and finding a home somewhere in the body (often the eye or the brain). They then make a cyst, and depending on where they happen to settle, they may be harmless or fatal. If a tapeworm presses against blood vessels, it can kill off tissue; if it causes inflammation in the brain, it can trigger epileptic seizures. If it finds a safer spot, it may go unnoticed for years. But unlike Toxoplasma, which essentially falls asleep in its cyst, Taenia remains active inside its shell. Through little pores in the cyst wall it sucks in carbohydrates and amino acids, and it grows.

A host’s immune system notices the arrival of a tapeworm egg and builds antibodies to it, but by the time it has become organized for an attack, the egg has disappeared; the larva has escaped and formed a cyst for itself. Immune cells crowd around the cyst and build an outer wall of collagen, and yet they can do nothing more. While the cyst takes in food it also releases over a dozen kinds of molecules, each of which stuns the immune system. Complement settles onto the cyst, but the tapeworm releases a chemical that binds to the molecule and stops it from combining into membrane-penetrating drills. The immune cells blast the cyst with highly reactive molecules that can kill tissue, but the tapeworm releases other chemicals that disarm them. And like Leishmania, the tapeworms can somehow jam the signals that would normally raise an army of inflammatory T cells. Instead, they encourage the immune system to make antibodies. There’s some evidence that suggests why tapeworms would go out of their way to do this. When the antibodies latch onto a cyst, the tapeworm drags them inside its shell and eats them. The tapeworm grows, in other words, by feeding on the futile efforts of the immune system.

Yet, like Toxoplasma, the tapeworm doesn’t want to kill its intermediate host. It’s only when the cyst begins to falter, when it can no longer hold out in the hope of getting into its final host, that it becomes dangerous. The tapeworm can no longer crank out the chemicals it uses to skew the immune system to antibodies. Now the immune system starts making inflammatory T cells tailored to the tapeworm, and they lead the macrophages and other immune cells into action. With such a huge target, the immune cells are worked up into a frenzy. They launch a violent attack that makes the tissue surrounding the cyst swell up, sometimes causing so much pressure that it can kill a person. It isn’t the parasite that kills the host, but the host itself.

An even more intimate knowledge of the human immune system can be found in the blood fluke, that passenger from Africa to Australia, that thirty-year-old Methuselah. When young flukes first penetrate the skin, they come to the attention of the immune system. Immune cells manage to kill some flukes early on, perhaps as the parasites struggle through the skin or as they pick their way through the lungs. But having cast off their freshwater coat, the flukes quickly put on a new one that the immune system never quite manages to figure out.

The reason their new coat is so confusing is that it’s partially made from the fluke’s host. You can see their disguise at work in a simple experiment. When parasitologists take a pair of the parasites out of a mouse and put them in a monkey, the flukes are unharmed and soon start churning out their eggs again. They aren’t so lucky if the scientists first inject antigens from mouse blood into the monkey. The injection acts like a vaccine, training the monkey’s immune system to recognize and destroy mouse blood antigens. If the flukes are transplanted from the mouse to the vaccinated monkey, the monkey’s immune system annihilates them. In other words, the flukes are so much like their mouse host that the monkey’s immune system treats them as if they were an organ transplanted from the mouse.

Even though the parasites in this experiment died, it demonstrated a brilliant disguise of theirs. Scientists aren’t sure how the flukes cloak themselves, but it seems that their coat is partially made out of the molecules studding our own blood cells. It may be that when the flukes pass by red blood cells or are attacked by white blood cells, they can tear out some of their host’s molecules and attach them to their own surface. Thus, to the eyes of the immune system, the parasites are nothing but red shadows in a red river.

These proteins aren’t the only things that blood flukes steal from our bodies. Complement molecules settle on the surface of our own cells just as they do on parasites. If they were allowed to go about their business of setting up beacons for macrophages, our immune systems would destroy our own bodies. To avoid this, our cells produce compounds such as decay accelerating factor (or DAF for short), which slices apart the complement molecules. Blood flukes can destroy the complement molecules that land on their own surfaces, and parasitologists have isolated the enzyme that they use. It turns out to be DAF.

It’s not clear whether the parasite steals it from its host’s cells or owns a gene for making the enyzme. It’s possible that at some point in the distant past, a virus that infected humans picked up the gene that makes DAF and then jumped to a blood fluke, adding the borrowed DNA to its new host. In either case, the molecule makes blood flukes as comfortable in our veins as the veins themselves.

In 1995, parasitologists studying blood flukes uncovered a paradox on the shores of Lake Victoria. They were studying Kenyan men who wash cars for a living along the lake. Working in the shallow water, they often get schistosomiasis, the disease caused by blood flukes. The prevalence of AIDS is high in the region as well, so that a fair number of the car-washers had both diseases. HIV destroys inflammatory T cells, the battle-hungry generals that lead macrophages against parasites. As these T cells die off, obscure parasites like Toxoplasma rampage through people with AIDS. Yet, blood flukes fare badly alongside HIV. In the Lake Victoria car-washers who had both AIDS and schistosomiasis, the blood flukes shed far fewer eggs than the ones in men who were sick with schistosomiasis alone.

The paradox of the car-washers stems from the fact that blood flukes need to use the human immune system to get their eggs out of their host. Without an immune system, they can’t reproduce. Once a female blood fluke lays her eggs in the vein walls, they begin secreting a cocktail of chemicals that manipulates the nearby macrophages. Under the spell of the eggs, the macrophages produce signaling molecules, the most important of which is called tumor necrosis factor alpha (or TNF-α). TNF-α is particularly good at causing inflammation by making the walls of the vein loosen up and by attracting more immune cells. The immune cells try to kill the egg with a spray of poisons, but the egg is protected by its tough shell. All the immune cells can do is wrap themselves around it, weaving an encapsulating shield of collagen.

The immune cells create this capsule (called a granuloma) in the hope of getting rid of the foreign object inside. If a splinter lodges in your thumb, for example, the cells will form a granuloma around it, which will then be carried up to the surface of the skin and be shed from your body. The same thing happens to a granuloma that forms around a fluke egg lodged in the wall of a vein. The granuloma moves through the vein wall and then through the wall of the intestines. This is exactly what the parasite needs to have happen, because it has to get out of its host’s body and hatch in water. The parasite, in other words, uses the white blood cells as porters to carry it across an impassable barrier. Once it’s on the other side, the immune cells in the granuloma are dissolved in the digestive juices of the intestines, but the tough-shelled egg survives and eventually tumbles out of the body. Hence the paradox of the car-washers of Lake Victoria: AIDS had robbed them of the immune cells the blood flukes needed to send off their young.

It’s an elegant way to multiply, but not a very efficient one. The flow of blood in the veins where the blood flukes live travels away from the intestines and up to the liver. As a result, it washes away half of the eggs before they can burrow out. They end up in the liver instead, where they form granulomas. But in the liver, the granulomas can do no good for the parasite, and they can end up killing the host. Parasitologists suspect that the blood flukes may actually keep their damage to their host under control by limiting their own numbers. Like their eggs, adult blood flukes also make the body produce TNF-α. The molecule doesn’t do much harm to the adults, but it is lethal to tender young larvae that have just invaded a person but haven’t had a chance to build their defenses. As a result, a person who already harbors blood flukes is far less likely to be infected with a new batch. Apparently, the blood flukes help the immune system attack latecomers of their own species to keep the host from getting overcrowded.

What’s most impressive about a blood fluke is not how many people it cripples or kills, but how it manages to thrive in the vast majority of its hosts while causing them only a little trouble. They are, in fact, selfish guardians.

Only vertebrates have the sort of immune system I’ve been describing up to this point, with its ever-adapting B and T cells. Invertebrate animals—everything from starfish to lobsters to earthworms to dragonflies to jellyfish—branched away from our own ancestors over 700 million years ago and evolved powerful defenses of their own. Insects, for example, bury intruders in a blanket of cells that ooze out poisons. Eventually the cells form a suffocating seal around the parasite. The parasites that specialize in invertebrates have adapted to their peculiar immune systems, with subterfuges as cunning as anything they use on humans.

One of the best-studied cases is that of the parasitic wasp Cotesia congregata. This mosquito-sized wasp uses the tobacco hornworm for its host, a tubby green caterpillar with black hooks on its feet and an orange prong sticking up from its back end like a horn. Scientists have studied this host and parasite so closely because the hornworm is a champion pest, devouring not just tobacco but tomatoes and other vegetables. It is also so big that scientists can simply mash it onto a slide to see what’s going on inside.

The attack of a Cotesia wasp is so fast you’re unlikely to catch it. It lands on a hornworm, crawls up its flank a short way, and stabs its egg-laying syringe into the host. The hornworm may squirm a bit to fight off the wasp, but to no avail. The wasp’s eggs hatch inside the hornworm as cigar-shaped larvae. They sip their host’s blood while breathing through silvery balloons of tissue on their back ends. The tobacco hornworm has a vibrant immune system, and yet the wasp young go about their business unmolested. But it’s not the larvae themselves that stop the immune system. For that, they need a gift from their mother.

The mother wasp injects the eggs as part of a soupy mix. The eggs depend on the soup for their survival: if you take out the eggs, clean off the soup, and then put them directly into a caterpillar, the host’s immune system rages full tilt and mummifies the eggs. The parasite survives thanks to millions of viruses swimming in the soup. These viruses are not much like the ones that we’re familiar with—the sort that cause a cold, for example. A cold virus wanders from host to host, invading the cells in the lining of the nose and throat, and then commandeering the cell’s own proteins in order to make new copies of the virus. Other viruses, like HIV, go so far as to stitch their genes into the DNA of their host cell and make copies of themselves from there. A few go even further: their hosts are born with the virus’s DNA already embedded in their own genes and transmit it to their children.

The viruses of parasitic wasps are stranger still. The wasps are born with the virus’s genetic code scattered across many of their chromosomes. In males the instructions stay in this scattered form. But as soon as a female begins to take its adult form in her pupa, the virus awakens. In certain cells of her ovary, the pieces of the virus’s genome are cut out of the wasp DNA and sewn together, like chapters assembled into a complete viral book. These genes then direct the formation of actual viruses—strands of DNA encased in a protein shell, in other words—and these viruses begin to load up inside the nucleus of the ovary cell. When the nucleus is filled to capacity, the entire cell bursts open, and millions of the viruses float free in the wasp’s ovary.

But they don’t make a female wasp sick. The wasp actually uses them as a weapon against the tobacco hornworm. When it injects the viruses into a caterpillar along with its eggs, the viruses start invading the host’s cells in a matter of minutes. They commandeer the host’s DNA, forcing the cells to make strange new proteins normally never seen inside a hornworm, which flood the body cavity of the caterpillar. These proteins destroy the hornworm’s immune system. The cells start sticking to one another instead of to the parasites, and then they burst open. The host is left as immunologically helpless as a person with full-blown AIDS (which is also caused by a virus that blows apart immune cells). Thanks to the virus, the wasp eggs can hatch and begin to grow without any harrassment by their host.

But unlike a person infected with AIDS, the hornworm recovers from the wasp virus after a few days. By then, the wasp larvae seem to be able to handle the immune system on their own, without help from mother. They may fool their host in ways similar to the ways blood flukes fool us, by borrowing the insect’s own proteins or by mimicking them.

It may seem perverse for a virus to do the dirty work for another organism, even going so far as wiping out a host’s immune system only to be wiped out itself. But within every egg that the virus protects, there are instructions for making new viruses that will survive if some viruses attack the host. At the same time, though, it may be wrong to think of a virus as a separate organism with its own evolutionary ends. The truth may be even more perverse, for the virus’s DNA resembles some of the wasp’s own genes. The resemblance may actually be hereditary: the virus may descend from a fragment of wasp DNA that mutated into a form that escaped from the normal way genes are copied and stored. It may not be strictly correct to call the viruses viruses at all—they may represent a new way that wasps package their own DNA. (One scientist has suggested calling the viruses genetic secretions.) If that’s the case, then parasitic wasps are managing to insert their own genes into another animal’s cells to make it a better place for the wasps’ to live.

These wasps may seem as if they belong on another planet, but they actually demonstrate a universal quality to parasites here on Earth: parasites find ways to battle immune systems, tailored precisely to the peculiarities of their host. Whether they end up killing or sparing their hosts depends on how they can best make more of themselves.