Brain Worms and Brain Amoebas

Parasites in the Brain?

At a recent evening lecture at the California Institute of Technology, a neurologist was explaining the ins and outs of new brain-imaging technology to an audience composed of Caltech professors, students, and members of the general public. The audience was rather quiet, lulled by the technical tone of the lecture. But when the neurologist mentioned in passing that the disease afflicting one of his patients was caused by a brain parasite, the whole room sat up and made a collective noise of disgust and alarm. Brain parasites!

But, in fact, parasites infect us all the time. They live in our bodies, even in our cells, and most of the time we do not even know that they are there. The brain can provide a pleasant, nurturing environment for parasites, because it has structures that prevent many of the immune system’s cells from entering, at least in the early stages of infection. Add to that plenty of oxygen and nutrients, and the brain seems like a rather nice place to live.

Despite its seemingly idyllic home, a brain parasite’s life does have its hardships. To begin with, the parasite has to find a way into the brain. Invasion of any organ is difficult, but the brain is an especially tough nut to crack due to a protective barrier between the bloodstream and brain fluid, called the blood-brain barrier. This barrier is made up of cells that make a tight seal along any blood vessels so that most stuff from the bloodstream (including brain parasites) can’t leak into the brain. If the parasite does manage to successfully enter the brain, it then has to deal with the attack of the immune system. The cells of the immune system act together to rid the body of any foreign organisms. In humans, the immune system is highly organized and efficient; parasites’ evasion mechanisms have evolved to be good enough to thwart the immune system, at least for a little while. Unfortunately, the most effective parasites are the ones we really have to worry about.

In fact, millions of people worldwide are infected by these efficacious brain parasites. If you haven’t heard about them before, it is probably because most infected people live in nonindustrialized countries, where living conditions are not very sanitary. Many of these brain parasites cause debilitating conditions and sometimes even death. So, in addition to being interesting biologically, brain parasites are also important in the context of human disease.

Two parasites with disease-causing capabilities are the pork tapeworm, Taenia solium, and the amoeba Naegleria fowleri. In addition to their medical importance, these two organisms illustrate the many ways that brain parasites are able to affect their hosts through their methods of invasion and survival.

Tapeworm: From Pork Chops to the Brain

The pork tapeworm is one of the most common disease-causing brain parasites. This parasite infects over 50 million people worldwide, and is the leading cause of brain seizures. It is usually contracted from eating undercooked pork, and once in the gut, it attaches to the intestine, and then grows to be several feet long. Under certain circumstances, these worms can also invade the brain, where thankfully they don’t grow to be quite so large.

Why does the worm sometimes attach to the intestine but at other times travel to the brain? It all depends on what stage of its life cycle the worm is in when it is swallowed. In its larval stage, the worm will hook onto the intestine; however, if eggs are swallowed, they hatch in the stomach. From there the larvae can enter the bloodstream and eventually travel to the brain. But in order to reach the brain from the bloodstream, the larvae must traverse the blood-brain barrier. Unfortunately, researchers still don’t know exactly how this happens. Many scientists think that the larvae can release enzymes that are able to dissolve a small portion of the blood-brain barrier to allow the parasite to get through into the brain.

Once the larvae reach the brain, they cause a disease called neurocysticercosis, by attaching to either the brain tissue itself, or to cavities through which brain fluid flows. (Brain fluid carries nutrients and waste to and from the brain, and acts as a cushion to protect the brain against physical impact.) Once attached, the larvae develop into cyst-like structures. The location of the cysts determines the symptoms exhibited by the host. If the larvae attach to the brain tissue, then the host often experiences seizures. This occurs partly because the presence of the larvae causes the activity of the brain to become wild and uncontrolled, thereby causing a seizure. On the other hand, if the larvae attach to the brain-fluid cavities, the host experiences headaches, nausea, dizziness, and altered mental states in addition to seizures. These additional symptoms occur because the flow of the brain fluid is blocked by the larvae. Often, the presence of the larvae also causes the lining of the brain-fluid cavities to become inflamed, further constricting the flow of the brain fluid. Since the cavities are a closed system, blockage of the cavities exerts pressure on the brain. This increased cranial pressure forces the heart to pump harder in order to deliver blood to the brain area, increasing the pressure on the brain even more. If the condition is not treated, the heart eventually cannot pump enough blood to the brain, neurons begin to die off, and major brain damage occurs.

[1st]: A pork tapeworm (Taenia solium) cysticercus, the form in which the tapeworm is found in an infected brain. (Colorized image by P. W. Pappas and S. M. Wardrop, courtesy of P. W. Pappas, Ohio State University.)

[2nd]: T. solium cysticerci in the brain of a nine-year-old girl who died during cerebrospinal fluid extraction to diagnose her headaches. This was in the 1970s—if it had happened 10 years later, noninvasive computerized tomography would have given an accurate diagnosis, and the parasites could have been killed with drugs. (Image courtesy of Dr. Ana Flisser, National Autonomous University of Mexico.)

It is interesting to note that some of these symptoms, such as seizures, are caused not only by the presence of the brain parasites, but also by the immune system. In general, parasites do not want to be detected by the immune system, because then they will most likely be eaten and killed. They try to do everything they can to avoid eliciting a strong immune response. Parasites also don’t want to do anything that can kill the host. If the host dies, then the parasites die too. For this reason, people can have parasites for years and not show any symptoms at all. But then, as the larval defenses break down, the host immune system is able to have a greater effect, and the symptoms become more obvious. What does the host immune system do to defend against the parasites, and why do its actions elicit harmful effects on its own body?

Defending the Body from Invaders

The main function of the immune system is to make

sure that any foreign object in the body is destroyed, including brain parasites. Many of the symptoms arising from brain parasite infection are due to the interactions between the immune system and the parasite. There are two main methods by which the immune system tries to rid the brain of the parasite. First, certain cells of the immune system make antibodies specifically against the parasite. Antibodies are molecules that can attach to a foreign organism and act like a signal flare, telling the rest of the immune cells that this organism is foreign and should be destroyed. There are also other immune cells, called phagocytes, which travel around the body eating anything that isn’t recognized as belonging to that body. These cells are much more effective at destroying germs that are labeled by antibodies. 

Second, there are proteins in the body that are able to recognize some general characteristics of many germs. These proteins make up the complement system. The complement proteins are able to attach to the germ and also act as signal flares to attract other immune cells that can destroy the germ. However, these proteins are sometimes also able to kill the germ themselves by forming a structure on the surface that can cut the germ open.

Why the Immune System Can’t “See” Tapeworm Cysts

The interaction between the immune system and the cysts is quite amazing; it is a great example of how evolution can produce two complementary systems. The immune system is seeking to find and destroy the parasite, while the parasite is attempting to stay hidden and alive. One way that the cysts are able to “hide” from the immune system is by degrading the antibodies that attach to them. There is some evidence that the antibodies are used as a food source, and that the cysts are able to coax the immune system to make more antibodies. The cysts can even disguise themselves as part of the host’s body by displaying proteins on their surfaces that identify them as part of the host—much as Wile E. Coyote hides from Sam Sheepdog in a herd of sheep by wearing a sheepskin. Finally, the location of the cysts is itself conducive to escaping detection by the immune system. The brain is not easily accessible to the cells of the immune system due to the presence of the blood-brain barrier, and so the parasites are partially protected from random encounters with the body’s defenders. Only when the immune response is in full swing can the immune cells enter the brain in large numbers.

Besides hiding from the immune system, the tapeworm parasites are able to prevent the immune cells from killing them by using several strategies. For instance, the parasites are able to prevent the complement proteins from attaching to their surfaces. The tapeworms can even release molecules that act as decoys, tricking the killer proteins into leaving them alone. The cysts also release other proteins that are able to protect them from being eaten, although how exactly this is accomplished is still unknown. There is some evidence that these proteins are able to prevent phagocytes from accurately targeting the cysts. One of the ways that phagocytes are able to go to the right place in the body during an infection is by following a chemical trail. This trail is produced by other immune cells at the site of infection. Some of the proteins released by the cysts are able to obscure this chemical trail so that the phagocytes become lost on their way to the infection. Cysts are also thought to release a second set of proteins that decreases the activity of new phagocytes. These proteins affect another group of immune cells that control the activity of new phagocytes; these regulatory immune cells then decrease the number of active phagocytes. Finally, a third set of proteins released by the cysts is thought to be able to prevent phagocytes from producing the proteins necessary to kill the cysts.

Victory?

The cysts are very successful in evading the immune system, but they gradually become more and more vulnerable to attack. As the immune system response gains strength, the most common symptoms of infection become more and more obvious. At first, the parasites are simply unable to hide from the immune cells, and cannot pretend to be part of the host’s body anymore. Then the full immune system response kicks in, and because the immune cells are able to detect the parasites, the parasites are doomed. More antibodies and complement proteins are released, more phagocytes are born, and more blood and immune cells rush to the parasitic sites. The areas where the parasites are located become swollen, which often leads to seizures and compression of the surrounding brain tissue. As the response progresses, the cysts are replaced by scar tissue, and finally by calcium deposits. (Calcium deposition often occurs in the body due to the activity of bacteria living in the blood, rather than as a direct effect of the immune system’s response.) The scar tissue and calcium deposits are also known to cause seizures. In addition, the immune response causes irreparable brain damage to the areas of the brain around the cyst as the phagocytes ingest the cells surrounding the cysts, which also contributes to the seizures.

Naegleria fowleri in the amoeboid form, near right, and in the cyst form, far right. The scale bar is 10 micrometers. Images courtesy of Bret Robinson, Australian Water Quality Centre and CRC for Water Quality Research.

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