Worms, Hormones, and Immune System

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Worm Uses Hormone Of the Immune System To Infect and Multiply

The New York Times
By GINA KOLATA
Published: August 4, 1992

ONE of the great unsolved challenges of biology is to understand how tiny pairs of parasitic worms, which live their entire lives copulating in a blood vessel, manage to escape all the body's defenses.

The worms somehow know exactly where to settle in and start mating. The thousands of eggs they release each day are somehow walled off by the body in tiny granulomas, masses of white blood cells, where they are protected from the immune system and the body is protected from toxins in the eggs. The entire system seems incredibly complex and almost impenetrable.

The lives and survival strategies of the worms are of more than academic interest. The worms cause schistosomiasis, a parasitic disease that has persisted for centuries and that afflicts an estimated 200 million people today. Even though there is a drug, praziquantel, that can cure the disease, people can be reinfected. And some people die because the drug is not available in many isolated areas.

"It's a disease that has been very difficult to control," said Dr. Alan Sher, a schistosomiasis researcher at the National Institute of Allergy and Infectious Diseases. Peeling Away Confusion

But now a group of researchers has, with a single stroke, peeled away layers of detail and confusion. They have revealed that at least one species of the worms, Schistosoma mannsoni, appears to recruit exactly the immune system hormone that white blood cells release as part of an inflammatory response. And the researchers hypothesize, the worms even use the hormone, tumor necrosis factor, to find the blood vessel where they will live to stimulate themselves to produce eggs and to force the body to encase their eggs.

"The worm has evolved to use immune system signals," said Dr. James H. McKerrow the University of California in San Francisco. The finding, by Dr. McKerrow and his colleagues was published in a recent issue of Nature, a British science journal. Although parasitologists said the discovery did not immediately suggest a a better drug or a vaccine for the disease, it showed a new direction for research.
Dr. Sher said the finding was a surprise. He added that before this no one had any idea what signals the worms needed to lay eggs. Dating to 2000 B.C.

The first written mention of schistosomiasis was in the time of the Egyptian pharaohs, around 2000 B.C. The disease was so common that infection with the parasite was considered a rite of passage and blood in the urine, a symptom of one form of schistosomiasis, was viewed as sign of puberty in boys.

Infected people excrete the microscopic, brownish-yellow eggs in their feces. If the eggs get into fresh water, the free swimming embryos escape, skittering about until they find a snail. They invade the snail and begin to multiply. Weeks later, thousands of larvae pour into the water.

When a person steps into the water the larvae rush over to burrow into the skin. From the skin, they enter the bloodstream and travel in it until they reach the lungs, where they stay for 10 days developing into white males and darker females. Then the worms re-enter the bloodstream. One species travels to the veins that drain the upper intestine, and another, Schistosoma mannsoni, goes to those that drain the lower intestine. Worms of a third species go to veins that drain the bladder. There they stay, copulating for the rest of their lives, which may be 20 or 30 years.

Each pair of worms excretes thousands of eggs a day. About half of the eggs burrow through the walls of the intestine or bladder, depending on the species, and are excreted and continue the organism's life cyle. The others are swept in the blood to the liver, where they are encased in granulomas.

It is easy to spot a granuloma-infested liver, said Dr. S. Michael Phillips of the University of Pennsylvania Medical School. The granulomas dot the liver, looking like raised white bumps the size of a pinhead.

"The granuloma looks like a ball," Dr. Phillips said. "In the center of the ball is an egg, and around the eggs are immune system cells."

But one mystery of granulomas was what made them form. The egg lodges in the liver, stimulates T cells, white blood cells of the immune system, to swarm to the scene, and then, said Dr. Sher, the T cells "bring in a whole bunch of other cells, almost like a cascade." The entire system looked incredibly complex.

And a mystery of egg production was what signaled it. Researchers could isolate adult worms and maintain them, still coupled, in the laboratory, but they ceased to secrete eggs.

An answer arose when Dr. McKerrow and colleagues decided to study an observation made earlier by Dr. Sher others that no one had pursued. The researchers had been studying a strain of mice without an immune system to learn how it affected the development of schistosomiasis. They noticed that the mice never excreted the worm eggs and did not make granulomas. But, the researchers found, when they provided the mice with white blood cells, they suddenly began doing so.

At that point, said Dr. Richard M. Locksley, a member of the group who is an expert on immune system hormones, they decided to ask whether it was the hormones the cells secrete, known as cytokines, that allowed the worms to make eggs. They added cytokine after cytokine until they hit on tumor necrosis factor.

The researchers discovered that when they dripped tumor necrosis factor on worms in the laboratory they laid eggs. When they infused the factor into infected mice with no immune systems, the mice excretedeggs and formed granulomas.

Dr. Locksley said the findings suggest a coherent story of how the worms survive and thrive. It begins with bacteria, which inhabit the intestines. These bacteria normally have endotoxins, poisons that are trapped in their cell walls. When the bacteria die, these endotoxins are released into the vein that carries blood from the intestine to the liver.

Macrophages in the vein come upon the endotoxins, sense a bacterial attack, and secrete tumor necrosis factor. So, Dr. Locksley said, there is always some tumor necrosis factor floating in that particular vein but the cytokine is not normally present in any other blood vessel in the body.

At the start of an infection, meanwhile, worms leave the lungs and float through the blood, looking for their final home. When they come upon tumor necrosis factor in a blood vessel, they remain there. The nutrients being carried from the intestine to the liver feed them. And the tumor necrosis factor that is always present stimulates them to lay eggs.

Some of those eggs float downstream to the liver. There, tumor necrosis factor is released by macrophages that creep through the tissue and initiate the formation of a granuloma. "Tumor necrosis factor recruits other cells and allows the granuloma to round off and get larger and wall off the egg," Dr. Locksley said.

As more and more eggs get encased in granulomas, the liver begins to swell and harden. Eventually, after many years, the liver function is severely impaired or destroyed. But, Dr. Phillips cautioned that even if this description was correct in all details, it was not yet clear how to use it to treat the disease. Although it might sound reasonable to give patients a drug that counteracts tumor necrosis factor, that could actually make matters worse, he said. The granulomas that eventually destroy the liver function also protect it from the worm eggs. "Eggs make substances that damage the liver," he explained. So to live with the worm, he said, "what you want is a very close balance between just enough of a granuloma to protect against the eggs but not so much response that products of the granuloma becomes pathogenic."

Still, Dr. Sher said, there is something intellectually pleasing about cutting thorough so much of the confusion and showing, he said, "that a parasite might be using a cytokine for part of its biology."



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