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 welclass="underline" 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.