Imagine a world without fear. It might be empowering to go about your daily life uninhibited by everyday distresses. You could cross highways with confidence, take on all kinds of daredevilry and watch horror flicks without flinching. Yet consider the prospect a little more deeply, and the possibilities become darker, even deadly. Our fears, after all, can protect us.
The basic aversion that a mouse has for a cat, for instance, keeps the rodent out of death's jaws. But unfortunately for mice everywhere, there is a second enemy with which to contend, one that may prevent them from experiencing that fear in the first place. A unicellular organism (a protozoan), Toxoplasma gondii, can override a rodent's most basic survival instincts. The result is a rodent that does not race away from a cat but is instead strangely attracted to it.
Toxoplasma's reach extends far beyond the world of cat and mouse. It may have a special relationship with rodent and feline hosts, but this parasite also infects the brains of billions of animals on land, at sea and in the air. Humans are no exception. Worldwide, scientists estimate that as many as three billion people may be carrying Toxoplasma. In the U.S., there is a one-in-five chance that Toxoplasma parasites are lodged in your neural circuits, and infection rates are as high as 95 percent in other countries.
For most people, this infection appears asymptomatic, but recent evidence shows that Toxoplasma actively remodels the molecular landscape of mammalian brain cells. Now some researchers have begun to speculate that this tiny single-celled organism may be tweaking human health and personalities in stealthy, subtle ways.
What the Cat Dragged In
Researchers first discovered T. gondii in 1908, and by the end of the 20th century they had a good grasp on how people could pick up this parasite. The story starts with cats: for reasons that scientists have yet to unravel, Toxoplasma can sexually reproduce only in the feline gut. The parasite breeds within its feline host and is released from the feline's tail end. Cats are such obsessive groomers that it is rarely found in their fur. Instead people can become infected from kitty litter or by ingesting it in contaminated water or food [see box on page 88].
Within a new host the parasite begins dividing asexually and spreading throughout the host's body. During this initial stage of the infection, Toxoplasma can cause the disease toxoplasmosis in immunocompromised or otherwise susceptible hosts, leading to extensive tissue damage. Pregnant women are particularly at risk. If a woman is infected with Toxoplasma for the first time during pregnancy, the parasite may invade the developing fetus, cutting through tissues and organs as it spreads from cell to cell. Infection early in pregnancy can result in miscarriage or birth defects.
In otherwise healthy individuals, however, the only symptoms during this period are brief, flulike discomforts such as chills, fever and body ache. Within days the immune system gets the parasite under control, and Toxoplasma retreats into a dormant state. It conceals itself within a hardened wall in the host's cells, a structure called a tissue cyst.
This stage of the infection has no other discernible symptoms, but individuals with dormant infections who develop compromised immune systems—because of AIDS, an organ transplant or chemotherapy—may experience severe complications. With the body's defense systems weakened, Toxoplasma can reactivate and grow uncontrollably.
Once infected, a person will remain a carrier for life. Our immune system is apparently incapable of eliminating the tissue cysts, nor can any known drug. Nevertheless, the infection, detectable with a blood test, has long been viewed as relatively benign. After all, many people carry this parasite with no obvious ill effects. Only recently have scientists begun reexamining this belief.
Eat Me, Mr. Kitty
In the 1980s researchers noticed unusual behaviors in Toxoplasma-infected mice. The rodents became hyperactive and groomed less. In 1994 epidemiologist Joanne Webster, then at the University of Oxford, observed that rats harboring tissue cysts behaved differently from their uninfected counterparts. Instead of fleeing from cats, the infected rodents moved toward them—making them easier prey.
Webster suspected that this “fatal feline attraction,” as she called it, was a crafty way for the parasite to get back into a cat's belly to complete the sexual stage of its life cycle. In the years to follow, this idea gained ground: a large body of work now shows that the parasite can indeed manipulate rodents' behavior by altering neural activity and gene expression.
Several well-controlled experiments have shown that although uninfected rodents avoid areas that have been infused with cat stench, infected rodents do not seem to mind. Even more bizarre, in 2011 neuroendocrinologist Robert Sapolsky of Stanford University, molecular biologist Ajai Vyas of Nanyang Technological University in Singapore and their colleagues found that—at least in terms of neural activity—infected rats appeared to be sexually attracted to cat scent.
In the mammalian brain, the “defensive” and “reproductive” neuronal pathways run in parallel. These pathways start at the olfactory bulb, involved in odor detection, and terminate at the limbic system, an area critical to basic reactions such as fear and arousal. Their proximity may partially explain how the parasite manipulates rodent behavior.
Working with 18 infected and 18 uninfected male rats, Sapolsky and his colleagues studied the rodents' behavior when they were exposed to either the odor of female rats or cat urine. Then they sacrificed the animals and looked at their brains. The researchers found a slight enrichment of parasite cysts in the limbic system compared with other brain areas.
They also assessed which parts of the brain had been operating during exposure to odors by staining the cells with a solution that revealed c-Fos, a protein expressed when neurons are active. The Stanford researchers discovered that infected rodents had high levels of engagement in their brain's reproductive pathway in response to the odor of both female rats and felines. In addition, the team found that infected rodents exposed to cat urine showed activation in the reproductive pathway similar to what uninfected rodents showed for the scent of a female rat. These results suggest that in infected rats, neural activity shifts from the defensive to the nearby reproductive pathway. Instead of smelling danger, the rats smell love.
Scientists are not sure how exactly the parasite elicits this fatal attraction, but one clue surfaced in 2014 in Vyas's laboratory. Vyas and his colleagues showed that Toxoplasma increases its host's levels of a neurotransmitter involved in social and sexual behavior. To accomplish this task, the parasite alters DNA methylation. Methylated genes are silent, blocked by a molecular cap. Toxoplasma uncaps a group of genes that spurs the creation of the sex-promoting neurotransmitter. Vyas and his team discovered this trick by performing the process in reverse: when they administered a chemical compound to the infected rats that silences the associated genes, the rats' peculiar attraction to feline odor vanished.
Kiss and Spit
With evidence mounting that Toxoplasma can influence its host's brain, other scientists set out to understand the parasite's effects at a much smaller scale: within each host cell. Their findings suggest that this microbe is particularly insidious—the changes it makes may be permanent.
To replicate, Toxoplasma must invade a cell. Stanford parasitologist John C. Boothroyd has dubbed this process “kiss and spit.” The parasite first attaches to the host cell (the kiss) and then releases an arsenal of foreign proteins into that cell (the spit). Toxoplasma then enters the host cell, and the injected proteins help it redecorate its new home.
The parasite's first act is establishing a protective bubble in which it can divide in peace without attacks from host cell proteins. (Later, during the infection's dormant stage, these bubbles thicken to become tissue cysts.) The parasite then moves the mitochondria, which serve as the cell's powerhouses, to be adjacent to the protective bubble. It also acts on the cell's DNA, inhibiting the expression of some host genes while activating others. Finally, Toxoplasma modifies host proteins to alter their function and inhibit the immune response.
Altogether, these modifications ensure that the host cell will live a long time and supply energy to the parasite, without alerting immune cells that a parasite has moved in. Although these findings have principally been made with rodents, work with human cell cultures suggests that the same changes probably take place in the human body. In our labs, we are studying how Toxoplasma replicates and interacts with its host in an effort to develop new drugs to treat this infection.
Remarkably, a study that Boothroyd's group published in 2012 showed that Toxoplasma not only spits into the cells it invades but also spits into cells that it does not infect. This behavior—spitting proteins in passing without lingering in the cells—is a recent discovery in the microbial world. Consequently, cells that are not harboring Toxoplasma contain parasite proteins that can co-opt and reprogram those cells. In the brains of infected mice, cells that have been spat into but not invaded are even more common than ones containing parasites. This widespread scattering of proteins means Toxoplasma can affect its host at a global level, making it easier to imagine how the parasite might manipulate the activity of an entire animal.
In 2013 biologist Michael Eisen of the University of California, Berkeley, and his colleagues found that a rodent's strange attraction to cat odors may be permanent, even if there are no longer signs of infection. In one study, Eisen exposed mice to a mutant strain of the parasite that does not appear to form brain cysts. Four months later the infected mice had no detectable parasites in the brain, yet they were still attracted to cat odors instead of repelled. This finding suggests that even if the parasite can be removed from the body, behavioral changes may persist. The infection leaves a mark, like a permanent parasite-given tattoo.
The Human Connection
The fact that people do not throw themselves into the lion cage at the zoo strongly argues that Toxoplasma does not affect humans in the way it transforms mice. Mammalian brains are not all the same, and Toxoplasma's tricks are most likely specially suited for rodents. The parasite has little to gain, in evolutionary terms, by adapting to control the human brain. We are, after all, a “dead-end” host—the parasites within us are unlikely to return to the cat gut for breeding. Nevertheless, these cysts lodged in our brains could be manipulating us in subtle, unexpected ways. For example, a recent study by epidemiologist Angelico Mendy of the University of Iowa found a potential link between Toxoplasma infection in children and performance on cognitive exams. A large body of research, mostly conducted by parasitologist Jaroslav Flegr of Charles University in Prague, supports the idea that Toxoplasma harbors the potential to change human behavior. In a series of personality assessments spanning more than a decade and involving nearly 2,500 individuals, Flegr and his colleagues found that certain traits often coincide with a Toxoplasma infection. For example, infected men tend to be introverted, suspicious and rebellious, whereas infected women tend to be extraverted, trusting and obedient.
Using a simple reaction time test, Flegr has also found that infected individuals are slower to respond than uninfected peers. This lag may relate to another correlation he has identified. In a 2009 analysis of 3,890 military conscripts in the Czech Republic, those with latent toxoplasmosis who also had a negative blood type, meaning they lacked the protein RhD, were six times more likely to be in a fender bender than those who were Toxoplasma-free or who had a positive blood type. The function of RhD is unknown. Flegr's results suggest RhD somehow protects people against Toxoplasma's effects, but how it does so remains a mystery.
More recently, Flegr and his colleagues found that some of the changes that occur in mice also exist in humans—albeit in a gender-specific manner. In 2011 the researchers asked 34 Toxoplasma-infected students and 134 noninfected students to rate the intensity and pleasantness of urine samples from different animals. Curiously, infected men found cat urine odor more pleasant than uninfected men; in women, the opposite occurred.
Another line of research has focused on a potential link between toxoplasmosis and schizophrenia. In 2001 psychiatrist E. Fuller Torrey of the Stanley Medical Research Institute and neurovirologist Robert Yolken of the Johns Hopkins University School of Medicine reported significantly more antibodies associated with Toxoplasma in patients experiencing their first schizophrenic episode as compared with healthy peers. Although this initial study was limited to only 38 people, additional studies in the ensuing years have largely supported this link.
Fascinating and attention-grabbing as these studies may be, they come with several caveats. The sample sizes are relatively small, meaning the findings are preliminary. They do not definitively demonstrate that Toxoplasma causes behavior changes in humans. In the case of schizophrenia, it is important to note that the condition is complex and may involve many triggers. The parasite may be one contributor, but it is also possible that people with schizophrenia may simply behave in ways that make them more likely to pick up an infection. No hard evidence has emerged to date that directly implicates the parasite as a cause for any psychosis, including schizophrenia.
Ultimately these provocative findings probably reflect a complex exchange among various factors. Certain genetic predispositions, for example, or even an interaction between Toxoplasma and another infectious agent could mean that some people are more susceptible to the parasite's persuasion. Only larger studies from multiple research groups will determine precisely what this parasite may do to the people it infects. Expanded studies might also help explain why Toxoplasma appears to have the opposite effects in men and women.
An Accidental Meddler
As researchers continue to uncover the astonishing effects that Toxoplasma has kept secret for so long, many scientists are beginning to think that Toxoplasma's impressive cellular and molecular tricks make it capable of causing disruptions within a human host. At the very least, the findings from human surveys call for further clarification.
If you are curious whether you carry the parasite, you can get a blood test. In the meantime, you can increase your odds of staying Toxoplasma-free by maintaining good hygiene for you and your feline friends. If cats wander through your yard, the Centers for Disease Control and Prevention recommends wearing gloves and a mask when gardening and keeping any sandboxes closed up when not in use. Other basic health tips—cleaning fruits and vegetables, thoroughly cooking meats and washing hands regularly—are also important for avoiding an infection.
The notion that Toxoplasma could radically reorient the brain and behavior is certainly disturbing. But perhaps these findings are a reminder of a more basic truth. Each person actually constitutes a rich ecosystem. For every human cell in the body, there are 10 more bacterial cells that influence physiology, metabolism and health. The protozoan Toxoplasma is just another stowaway within the system and one that warrants more study. After all, we will never fully understand ourselves without learning about our microbial companions.
How Toxoplasma Conquered the Animal Kingdom
Toxoplasma gondii is the most widespread parasite on earth, found across all continents and in a staggering variety of habitats. We have only recently discovered how many different animals it infects. To the surprise of many, University of British Columbia scientists found the parasite in beluga whales in the Arctic in 2014. Off the California coast, Toxoplasma infection has been revealed to be responsible for sea otter deaths formerly attributed to sharks or boats.
The wily intruder owes its success in part to a high rate of expansion. A cat newly infected with Toxoplasma can excrete up to 800 million packets containing the parasite—called oocysts—in the span of about seven to 14 days. Once released, an oocyst can persist in soil or water for years. Inhaling or ingesting just one oocyst is enough to establish infection, which virtually guarantees that the parasite will find its way into a variety of new hosts.
But house cats may have unfairly gotten a bad reputation from their link toToxoplasma. Pet owners may indeed accidentally ingest an oocyst if they fail to wash up after tending to kitty litter, but scientists believe an individual cat will shed oocysts only once in a lifetime.
In contrast to housebound felines, wild and feral cats can spread oocysts in gardens, farms and water reservoirs, meaning they are likely to be greater contributors toToxoplasma's spread. Oocysts are commonly found in dirty water or on unwashed fruits and vegetables. The parasite does not infect plants, but its oocysts can remain on their surface unless they are carefully cleaned.
Moreover, many animals—including humans—are likely to become infected by eating raw or undercooked meat. Any animal infected by Toxoplasma will harbor tissue cysts for the rest of its life. When that tissue is eaten in, for instance, steak tartare, the para-site spreads into its new host. These clever methods of entering new hosts have allowed Toxoplasma to disseminate across the globe. —G.S. and B.S.