Brain Worms And Brain Amoebas

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http://pr.caltech.edu/periodicals/eands/articles/LXVI4/brainworms.html

 

 

Brain Worms And Brain Amoebas

 

By Andrea Manzo

 

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.

 

Top: 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.) Bottom: 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.

 

In fact, more harm than good often comes out of the immune response to

infection of the brain by tapeworms. Against most pathogens, however,

the immune response is actually beneficial to the body. Foreign

organisms often cause lots of damage, and it is important that they be

destroyed as quickly and efficiently as possible. Furthermore, the

immune system response is generally the same regardless of the

identity of the foreign invader; and in most circumstances, the immune

response does not have negative effects. Overall, the immune system is

actually highly effective at defending the body from foreign organisms.

 

Of course, the effectiveness of the immune system is largely dependent

on the ability of the body to mobilize its defenses. Some parasites

act so quickly that the immune system is unable to react before the

infection becomes fatal. One such brain parasite is Naegleria fowleri,

a water-borne amoeba.

 

Danger in the Waters

 

If you've never heard of Naegleria fowleri, don't be surprised. Unlike

the pork tapeworm, N. fowleri has only infected about 175 people in

the world, causing a disease called primary amoebic

meningo-cephalitis. But out of those 175 people, only six have

survived, giving a mortality rate of 97 percent. For this reason, it

is quite an important parasite to study, as there are no current

treatments that have proven effective against it.

 

Fortunately, natural infection by the parasite is very rare, although

N. fowleri is ubiquitous in the wild. It lives mostly in warm

freshwater lakes and ponds, but can even thrive in heated swimming

pools. Furthermore, N. fowleri is actually a free-living organism,

which means that it can survive without a host. This explains why N.

fowleri attacks are so rapidly fatal—since hosts are not necessary to

its survival, the parasite does not have to take pains to avoid

killing them.

 

Part of the reason that N. fowleri can survive in such numbers and in

so many different places is because it is an amoeba. Amoebas are

single-celled creatures that resemble sacks of fluid gelatin

surrounded by a greasy membrane. Because of their small size and few

requisites for survival, these organisms are found everywhere. In

addition, the amoebas can form cysts in harsh conditions like extreme

cold; in this form, they are protected against the environment.

 

Attack of the Amoebas

 

When an amoeba invades a person, it is normally in its active,

reproductive phase. Invasion occurs when the amoeba attaches to the

inside of its host's nose and then travels up the nose to the brain.

The amoeba follows the path laid out by the olfactory nerve, although

sometimes it can also use the bloodstream. Several enzymes released by

the amoeba are able to dissolve the host's tissues, giving access to

the brain. Once in the brain, the amoeba causes damage by actually

eating the nerve cells. As you can imagine, this is very harmful to

the host, and is the main reason why infection by N. fowleri causes

such rapid death. The amoeba is able to eat neurons because it has

surface proteins that allow it to cut a hole in the covering of the

cell. The contents of the neuron leak out, and the amoeba can feed on

the nutrients it contains. The amoeba even has proteins on its surface

that tell it where the best food sources are. These proteins are able

to sense the presence of certain nutrients, and then send signals to

the rest of the cell indicating in which direction the amoeba should

move to eat those nutrients. Finally, there are other proteins on the

amoeba's surface that direct it to the most vulnerable areas of a neuron.

In addition to causing direct brain damage by ingesting neurons, the

presence of N. fowleri amoebas can cause inflammation of the

brain-fluid cavity linings. Similarly to infection by tapeworm,

blocking the brain fluid can cause increased pressure on the brain.

However, this effect is usually only secondary to the much more

destructive digesting action of the amoebas.

 

Brain tissue infected by Naegleria fowleri. The dark dots are the

amoebas. Notice the empty space around the dots; this space used to be

tissue before the amoebas digested it. Image provided by the Division

of Parasitic Diseases, Centers for Disease Control and Prevention.

 

Fighting the Invader

 

The immune system, however, is not completely idle while this invasion

and destruction is occurring, although for the most part its efforts

are in vain. The amoebas use several strategies to stave off the

immune cells. Many of these strategies are similar to those used by

tapeworm cysts. For example, the amoebas are able to internalize

antibodies on their surfaces, although they don't need these

antibodies as a food source. Other proteins on the amoeba's surface

prevent the attachment of complement proteins. If the complement

proteins are able to bypass these surface proteins, the amoeba is able

to collect them in one area of its membrane. Afterwards, the amoeba

can shed that piece of the membrane. The shed membrane acts as a

decoy, attracting more complement proteins that would otherwise attack

the amoeba.

 

Why are these strategies effective in shielding the amoebas, but not

tapeworms, from the immune system? The reason is that an amoebal

infection is rapidly fatal. The immune system does not have time to

fully mobilize its immune cell armies before the brain damage is so

extreme that the organism dies. Since these amoebas don't need the

host to survive, it's not a big deal if they kill him or her off.

Tapeworms, however, die when the host does, and so they try very hard

to keep from being detected by the immune system. And in fact, they do

a fairly good job at that, since most tapeworm infections aren't

noticeable until many years after the tapeworms get into the brain.

The immune system is only able to have a big effect on the infection

when the tapeworms start to die, often from old age.

 

Parasite Evolution

 

These two parasites offer only an inkling of the many organisms that

can infect the human brain. While the two seem to differ greatly, the

molecular weapons they use for defense and invasion are really very

similar. For instance, there is evidence that both parasites use

enzymes to penetrate the blood-brain barrier, and both use a decoy

strategy to deflect the attention of the immune system. This

similarity results from evolution, which has slowly altered these

parasites so that they are as effective as possible at survival. As

new treatments and cures of brain-parasite-related diseases become

available, it will be interesting (as well as medically useful) to see

how the strategies of these parasites change.

 

Andrea Manzo is a senior majoring in biology. She decided to find out

more about brain parasites after attending the 2002 Biology Forum,

" Gray Matters: Perception, Intention, Memory, and Dysfunction in the

Brain, " but is currently doing a research project on neural-crest cell

development in chick embryos, a subject with a much lower yuk factor,

in the lab of Ruddock Professor of Biology Marianne Bronner-Fraser.

Andrea is also house secretary and webmaster of Ricketts. Her faculty

mentor on the Core 1 paper was Jed Buchwald, the Dreyfuss Professor of

History (see page 20), and the editor was Gillian Pierce.