Parasites Practicing Mind Control

An unassuming single-celled organism called Toxoplasma gondii is one of the most successful parasites on Earth, infecting an estimated 11 percent of Americans and perhaps half of all people worldwide. It’s just as prevalent in many other species of mammals and birds. In a recent study in Ohio, scientists found the parasite in three-quarters of the white-tailed deer they studied.

One reason for Toxoplasma’s success is its ability to manipulate its hosts. The parasite can influence their behavior, so much so that hosts can put themselves at risk of death.

Scientists first discovered this strange mind control in the 1990s, but it’s been hard to figure out how they manage it. Now a new study suggests that Toxoplasma can turn its host’s genes on and off — and it’s possible other parasites use this strategy, too.

Toxoplasma manipulates its hosts to complete its life cycle. Although it can infect any mammal or bird, it can reproduce only inside of a cat. The parasites produce cysts that get passed out of the cat with its feces; once in the soil, the cysts infect new hosts.

Toxoplasma returns to cats via their prey. But a host like a rat has evolved to avoid cats as much as possible, taking evasive action from the very moment it smells feline odor.

Experiments on rats and mice have shown that Toxoplasma alters their response to cat smells. Many infected rodents lose their natural fear of the scent. Some even seem to be attracted to it.

Manipulating the behavior of a host is a fairly common strategy among parasites, but it’s hard to fathom how they manage it. A rat’s response to cat odor, for example, emerges from complex networks of neurons that detect an odor, figure out its source and decide on the right response in a given moment.

Within each of the neurons in those networks, thousands of genes are producing proteins and other molecules essential for relaying all of the necessary information throughout the body. Simple Toxoplasma seems ill-equipped to take over such a complicated system.

But a new study published in the journal Molecular Ecology hints that the parasite can do so by relying on an eerily elegant strategy. Think of the genes in a host as keys on a piano. Toxoplasma, it seems, simply plays some of the keys differently to produce a new melody.

A rat is made up of lots of different kinds of cells, from the neurons in its brain to the bone-producing cells in its skeleton to the insulin-making cells in its pancreas. Yet all of them carry the same 20,000 genes. Depending on the function of a particular cell, some of its genes are switched on and others are shut down.

Genes may be switched off, or silenced, by the attachment of molecular caps called methyl groups, a process called methylation. In order to switch a gene on again, the caps are removed.

Methylation does more than just allow cells to develop into a variety of organs. It lets them change the way they work in response to signals from the outside. In the brain, for example, neurons rely on this process to lay down long-term memories and change how an animal responds to its environment.

Ajai Vyas, a neurobiologist at Nanyang Technological University in Singapore, wondered if Toxoplasma might wreak changes on rats by changing methylation in the rat brain — an idea “just hiding in plain sight,” he said.

In earlier research, Dr. Vyas and his colleagues had found that infected rats produced extra amounts of a neurotransmitter called arginine vasopressin. The neurotransmitter is manufactured by a small set of neurons buried in a structure of the brain called the medial amygdala.

Perhaps, Dr. Vyas thought, the parasite switched on the gene for arginine vasopressin in those cells. To find out, he and his colleagues ran a series of tests.

First they looked at the gene for arginine vasopressin in the medial amygdala of rats. In infected rats, they found, many of the molecular caps were missing, suggesting that Toxoplasma had “unsilenced” the gene in order to increase production of the neurotransmitter. The arginine vasopressin then might alter their response to cats.

If that were true, Dr. Vyas reasoned, then counteracting the parasite’s strategy should change the rat’s behavior.

He and his colleagues injected an extra supply of the molecular caps into infected rats. Some of the caps attached to the arginine vasopressin gene, and the rats became more fearful of the odor of cats.

That experiment led Dr. Vyas to see if he could make the rats behave as if they were being controlled by parasites — but without the parasites.

He and his colleagues removed molecular caps from the arginine vasopressin gene, mimicking what Toxoplasma might be doing to its hosts. The rats became reckless, feeling no fear at the whiff of cats.

“The animals looked like they were infected, even though there was no parasite around,” said Dr. Vyas.

“I think they could be on to something interesting,” said Michael Eisen, a biologist at the University of California, Berkeley, who has researched Toxoplasma in mice and was not involved in the new study. But he thought more experiments would have to be done to make a compelling case that the parasites really are using methylation to control their hosts.

Kami Kim of Albert Einstein College of Medicine, who also was not involved in the study, was more enthusiastic about the research. She also suggested that the strategy may be not be uncommon. In a review published this spring in the American Journal of Pathology, Dr. Kim and her colleagues survey a number of species that may use methylation to turn host genes on and off.

The bacteria that cause leprosy, for example, invade certain kinds of neurons and change some of their molecular caps. This methylation causes the neurons to change into stem cells much like those in an embryo. In this new state, the infected cells leave the nervous system and migrate through the body, spreading the bacteria with them.

“It looks like it will be a general strategy used by pathogens,” said Dr. Kim.