Photograph by AJ Cann
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Toxoplasma gondii
Photograph by AJ Cann

Mind-Bending Parasite Permanently Quells Cat Fear in Mice

A mouse sniffs the air, catches the whiff of cat urine, and runs towards the source of the smell… and straight into the jaws of a cat. This bizarre suicidal streak is the work of a single-celled parasite called Toxoplasma gondii, which has commandeered the mouse’s brain and turned it into a Trojan rodent—a vehicle for sneaking T.gondii into a cat.

T.gondii (or Toxo for short) infects a wide variety of mammals, but it only completes its life cycle in the guts of a cat. To get there, Toxo has ways of subverting the behaviour of dead-end hosts like mice. Its machinations are subtle, so subtle that it’s normally hard to tell an infected mouse from an uninfected one. But the difference becomes obvious when there’s cat pee in the air. Normal mice, even lab-born ones that have never met a cat, have an innate fear of cat smells. Those infected with Toxo do not. They (and their parasites) are more likely to end up in a cat.

Toxo also influences the brain of Wendy Ingram from the University of California at Berkeley. She has long been obsessed with the brain and fascinated by Toxo’s dominion over it. “I was struck by the idea that a single celled parasite ‘knows’ more about our brains than we do,” she says. Working as a PhD student in the labs of Michael Eisen and Ellen Robey, Ingram started trying to understand how Toxo affects the brains of rodents. And her experiments already promise to revise what we know about this mind-bending parasite.

Once Toxo gets inside a brain, it can ensconce itself within neurons and create dormant cysts. In this form, it can stay with a host for its entire life. Some scientists have suggested that the parasite then releases substances that affect specific parts of the brain, like those involved in fear or sexual arousal. But Ingram has found that Toxo’s presence is unnecessary. Even if rodents no longer show traces of the parasite, they’re still unafraid of cat smells! Whatever Toxo does, it seems to do it permanently.

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Parasite lost

This type of experiment would normally be hard to do. Most rodent experiments use the Type 2 strain of Toxo (there are three major strains in Europe and North America), which produce a lot of cysts. And once the parasite holes up, there are no cures that can get rid of it. But Ingram worked with a mutant version of the Type 1 strain, which neither forms cysts nor causes long-term infections.

Ingram found that this strain also neutralised a mouse’s fear of cats. When placed in a darkened box, normal mice will stay away from a dish of bobcat urine, but will happily wander near a dish of rabbit urine. But when infected by Toxo—any strain of Toxo—they’ll blithely wander near the bobcat pee too. That’s not because their sense of smell doesn’t work—they could still detect the aromas of a hidden cookie. It’s because Toxo specifically befuddles their cat-dar.*

After four weeks, Ingram couldn’t detect any traces of the parasite in the brains of the once-infected mice. She searched for Toxo DNA and couldn’t find any. She measured the number of white blood cells in the brain, which would indicate an ongoing infection, and saw that it had fallen to normal levels. The mice had effectively been “cured” of Toxo, but they were still unperturbed by cat urine.

But Glenn McConkey, a Toxo researcher from the University of Leeds, isn’t convinced that the mice were completely Toxo-free. He says that the team’s methods were “unlikely to be sensitive enough for very low detection levels”. They should have checked their results by exposed healthy mice to brain tissues from supposedly cured ones.

Ingram acknowledges that her methods might have missed a lone remaining parasite, and she didn’t look at muscles or testes where Toxo sometimes hides. But she adds, “We can say with confidence that there are very few, if not zero, parasites in the brains of these mice.”

“This is a very important result with enormous implications for understanding the previously published data in rodents,” says John Boothroyd from Stanford School of Medicine, who has advised Ingram on her research. Most people have assumed that Toxo produces substances that change a rodent’s behaviour. If that’s right, Ingram’s study suggests that this mystery substance is either very long-lived, or so profoundly rewires the host’s brain that its effects get locked in even in the parasite’s absence.

Boothroyd likes the latter idea. His own lab has shown that Toxo “touches” many more neurons than it actually infects. It might not physically enter a cell, but it can still inject proteins inside, and these can permanently switch on genes. “Perhaps one of those injected proteins rewires a neuron permanently”, he says.

To Ingram, this is one of many possibilities, including some that no one has even thought of yet. “I think that it would be a bit presumptuous of us to think we can guess how biological systems interact, especially those as complicated as parasites and hosts,” she says. “For me, it is still early in the detective work, picking up clues.”

She suspects that Toxo may work its influence by affecting a rodent’s immune system—after all, the brain has its own resident fleet of immune cells whose effects on behaviour is poorly understood. “Toxoplasma is equipped with a number of tools that directly affect or hijack immune cells in the rest of the body, says Ingram. She is now planning a new wave of experiments to tease apart these effects, while collaborators focus on what the parasite does to neurons.

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Cyst in mouse brain, containing thousands of parasites. Credit: Jitinder P. Dubey

Toxo and humans

Does this have any relevance for humans? It depends on whom you ask. One in three people around the world carry the parasite (although the proportion varies a lot between countries), and some scientists have suggested that Toxo can affect human personality, behaviour, or even mental illness.

This field is rife with tenuous evidence, but the most compelling set of data concerns schizophrenia. There are many studies showing that people with schizophrenia are more likely to be infected by Toxo, and a couple which show that infection precedes the onset of symptoms. But even this connection is controversial. After all, Toxo is very common and schizophrenia is very rare. Psychiatrist Fuller Torrey has been studying this link for many years. When I last spoke to him about it, he said, “I don’t think anyone will believe the story until we show that if we treat the organism, the symptoms will improve. That’s the ultimate proof.”

But even if that were possible (remember: there are no cures for Toxo), Ingram’s study might throw a spanner into the plan. “We cannot assume that clearing a particular infection can undo the effects on targeted cells or the host immune response,” she says.

Ingram doesn’t think the schizophrenia connection is strong enough yet. But she suspects that there might be many temporary infections that cause permanent changes in behaviour, and affect the risk of complicated and long-term diseases. She imagines a future where doctors look at a patient’s set of antibodies to take a molecular medical history of their past infections. “Whether those microbes result in persistent infection or are cleared, we would have a new level of understanding the person’s current biology in the context of their entire lives,” she says.

For now, Ingram has posted her a pre-print of her results on arXiv—an open-access hub for scientific papers—while they are being peer-reviewed for PLoS ONE. Eisen has also blogged about the work and is welcoming comments on the paper, as part of the lab’s commitment to open science.

“I’ve already received a number of extremely useful correspondences from fellow Toxoplasma researchers,” says Ingram. “We’re in a beautiful age of accelerated communication. Open-access science and immediate dissemination of the latest research using venues such as ArXiv will only lead to more efficient scientific advances.”

Reference: Ingram, Goodrich, Robey & Eisen. 2013. Low-virulence Strains of Toxoplasma gondii Result in Permanent Loss of Innate Fear of Cats in Mice, Even after Parasite Clearance. arXiv:1304.0479

* Toxo-infected mice are insensitive to the urine of all cats, whether tigers or domestic tabbies. Other scientists have shown that they’re still repelled by dog urine, although Ingram couldn’t corroborate that. She did find that even uninfected mice don’t care about the smell of mink, fox, wolf, coyote and hyena urine. And she adds, “I do happen to have bear urine, which I have not tested yet.”

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