A Common Parasite Reveals Its Strongest Asset: Stealth

 
By CARL ZIMMER
June 20, 2006:-  On paper, Toxoplasma gondii looks as if it ought to be the most famous parasite on earth. This single-celled pathogen infects over half the world's population, including an estimated 50 million Americans. Each of Toxoplasma's victims carries thousands of the parasites, many residing in the brain. As if that were not enough of an accomplishment, Toxoplasma is equally adept at infecting all other warm-blooded animals, as disparate as chickens and kangaroos.

Scientists are now discovering some of the secrets of Toxoplasma's success. Researchers in Sweden report that the parasite fans out through the body by manipulating mobile cells that are part of the immune system. Toxoplasma hijacks these so-called dendritic cells and makes them race around the body and ignore commands from other immune cells to commit suicide. The dendritic cells sneak the parasites into the brain and other organs, acting much like a Trojan horse.

Strategies like this one have made Toxoplasma incredibly widespread and incredibly obscure. Mention the parasite to most people and chances are you will draw a blank. Pathogens that infect far fewer people, like the Ebola and West Nile viruses, are far more famous.

Toxoplasma's obscurity is in fact a great tribute to its powers. "To the parasite's credit, it's incredibly successful," said Dr. Lloyd Kasper of Dartmouth University. "It's adapted itself to be a benign infection."

For the vast majority of people, Toxoplasma causes no serious effects. It manages this feat by hijacking our cells and immune system, and establishing a careful harmony between parasite and host. "Once you get infected with Toxoplasma, you're infected for life," Dr. Kasper said.

Toxoplasma can, however, cause serious brain damage in those with weak immune systems, like fetuses and adults with AIDS.

Cats play a major role in the parasite's success. They can carry it in their intestines, where they can produce egglike cysts called oocysts. A single infected cat can shed 100 million oocysts in its droppings. The oocysts can survive in the soil for over a year and can contaminate drinking water.

Oocysts can infect humans, as well as other mammals and birds. Undercooked pork, chicken and other meat is another route Toxoplasma can take into our bodies.

Once Toxoplasma enters a host, it spreads quickly. Within hours it can be detected in the heart and other organs. It is even able to infect the brain, which is protected from most pathogens by a tight barrier.

Antonio Barragan and his colleagues at the Karolinska Institute in Stockholm were puzzled at first about how Toxoplasma managed this swift journey. "When we looked for parasites in the blood, we found very few that were just swimming around," said Dr. Barragan, an associate professor. But the scientists observed many of the parasites inside immune cells known as dendritic cells.

Dr. Barragan was intrigued. Dendritic cells, common in the gut, often come into contact with pathogens. They respond by crawling to the lymph nodes or the spleen, where they communicate with other immune cells.

"That led us to think, what if this parasite is directing these cells to move and to disseminate through the body?" Dr. Barragan said. He and his colleagues put dendritic cells in a dish and injected them with Toxoplasma. They noticed that the parasites triggered a peculiar change: the dendritic cells became hyperactive, crawling for an entire day.

Next, the scientists observed how Toxoplasma spread through a living animal. They added a firefly gene to the parasites so that they produced a glow. When they injected the parasites into mice, a little of the light escaped from the animals. By putting the mice in a darkened box, Dr. Barragan and his colleagues could track the parasites as they spread.

Injecting dendritic cells carrying Toxoplasma spread the parasites to the brain and other organs far faster than injecting Toxoplasma alone. The researchers concluded that Toxoplasma was taking charge of the dendritic cells and riding along with them. Their results are published online in the journal Cellular Microbiology.

As Toxoplasma spreads through the body, it invades cells. Unlike other pathogens, Toxoplasma can enter almost every type of cell in the bodies of thousands of host species. The parasite slips into a cell by latching onto its surface and pulling the membrane over itself. "You can think of it like sticking your finger into a balloon," said Vernon B. Carruthers of the University of Michigan.

David Sibley, an associate professor of molecular microbiology at Washington University in St. Louis, said, "It just sits there, and the host doesn't recognize it as a foreign body it should destroy."

If Toxoplasma simply spread from cell to cell, it could cause serious harm. But killing its host is not in the parasite's best interests: its goal is to get into its final host, cats, the only creature in which Toxoplasma can reproduce by making oocysts that are shed in feces. And cats do not like eating dead animals. Instead, Toxoplasma has evolved to be extremely contagious, but not very harmful.

"This is an organism that has very cleverly worked out a way to go from one host to another," said Alan Sher, chief of the Laboratory of Parasitic Diseases at the National Institutes of Health. Dr. Sher studies how Toxoplasma manipulates its host's immune system. In the early stages of infection, the parasite sets off the production of signaling molecules called cytokines. They cause the immune system to attack Toxoplasma, killing off free-floating parasites.

The parasites that happen to be inside cells during the attack somehow recognize what is happening and enter a kind of hibernation. Their host cell turns into a cyst in which they can hide from the immune system.

The strong response Toxoplasma provokes from the immune system carries a risk of its own. "These cytokines just get out of control and cause tissue damage," Dr. Sher said. In experiments with mice, this response can be fatal, he said.

Toxoplasma steers its hosts away from this danger, Dr. Sher has found. It causes its host to make molecules that rein in the immune system.

An infection with Toxoplasma may feel like nothing more than a mild case of the flu, and the symptoms pass once the parasite has snuggled itself away in its cysts. In later years, cysts occasionally break open, but the immune system quickly destroys most of the free parasites. The few survivors invade new cells.

"That's the key of this infection," Dr. Barragan said. "I think this is why this parasite is so tremendously successful worldwide."

Toxoplasma becomes a menace when it does not have a healthy immune system to control. Pregnant women infected for the first time by Toxoplasma may pass it to their unborn children. Without a strong immune system to keep the parasite in check, a fetus can suffer massive brain damage. Up to 4,000 children are estimated to suffer toxoplasmosis in the United States each year.

Toxoplasma is also dangerous to adults with weakened immune systems. The cause may be AIDS or immune-suppressing drugs given to people who receive organ transplants. A quiet Toxoplasma infection can suddenly explode.

For decades, most scientists believed that people with healthy immune systems had no effects from Toxoplasma. But some studies in recent years have hinted that the parasite can exert surprising effects on behavior, at least in animals.

In 2000, British scientists demonstrated that rats infected with Toxoplasma lost their fear of cats. They proposed that this strategy increased the parasite's chances of getting into its final host.

Scientists at Stanford University recently followed up on these experiments, studying rats and mice. "They actually show a mild attraction to the cat odor," said Ajai Vyas, a Stanford neurobiologist. "It's not just the loss of an old behavior. A new behavior is being induced."

Dr. Vyas and his colleagues found that Toxoplasma's effects were precisely aimed at cat odor. The rats were still afraid of dog odor but not of rabbit odor. They could also acquire new fearful responses. "Only the innate fear to the cat was different, which was very surprising," he said. "We don't really know how fear of a cat is hard-wired in the brain."

How Toxoplasma incites this change is a mystery. It is possible that the parasite alters the production of certain neurotransmitters. "But I don't know how some global change could have such a specific effect," Dr. Vyas said. He reported his results in May at the annual meeting of the International Behavioral Neuroscience Society.

Some scientists suspect Toxoplasma may influence the human brain. Several studies suggest a correlation between Toxoplasma and schizophrenia, but the claims for a connection are not widely accepted.

Dr. Robert H. Yolken, the director of the Stanley Laboratory at Johns Hopkins University, and his colleagues reviewed military medical records. They found that soldiers who developed schizophrenia were twice as likely as other soldiers to show signs of Toxoplasma infection in blood samples.

Toxoplasma's dangers, both proven and potential, are cause for concern, experts say. "It's a substantial public health risk," Dr. Sibley said.

Recent studies suggest that Toxoplasma is rare in meat sold in stores in the United States. However, experts still recommend cooking meat thoroughly to kill any parasites.

Dr. Milton M. McAllister, a parasitologist at the University of Illinois at Chicago, has called for controlling the spread of Toxoplasma by cats. He notes that oocysts from cats can also infect wildlife. Toxoplasma has even been detected in sea otters, suggesting it can reach the ocean.

"It's perfectly safe to keep a cat," he said. "Just keep it inside."

From:   http://www.nytimes.com/2006/06/20/science/20toxo.html?ex=1150948800&en=6bcbdb3f24344d82&ei=5087%0A