Microbes with mind-control

Wendy Zukerman takes stock of the bugs that can make us crazy.

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The moment the parasite entered his brain, he was doomed. All he did was eat some tasty bird faeces which, rather unfortunately, were infected with the parasite Leucochloridium paradoxum. The parasite quickly multiplied inside him, transforming into a swarming horde writhing towards his head. Once there, the parasitical mass squeezed into his eyestalks and distended them until they looked like green and yellow striped caterpillars. Meanwhile, the parasite set to work taking control of the snail’s simple brain, forcing him to climb high above the leafy canopy into the bright sunshine.

It’s a dangerous place for a snail. Sure enough, a bird swept in to claim the tasty morsel. It’s a job well done for L. paradoxum, which can now lay eggs inside its new avian home.

“Students gasp every time they see it,” says Robert Poulin, a parasitologist at the University of Otago in New Zealand. While he says “the behaviour of the zombie snails, to climb a little higher, is not too striking”, the bug’s powers of manipulation are spectacular and as he points out, if it weren’t for the snail’s strangely striped tentacles, scientists may never have realised what was going on. That raises the question: what other parasites are quietly manipulating their victims? Could they be manipulating you and me?

An array of microbes including viruses, bacteria and single-cell protozoa have been found to get into the heads of their hosts and alter their behaviour. The more we look, the more cases we find. So why should human minds be immune?

Of course they aren’t.

Tanya Cooper

The classic example of a bug that manipulates human minds is lyssavirus, the agent behind rabies. Transmitted by the bite of an infected animal, it tracks up the nerves of a bitten limb until it reaches the brain. From there it provokes its victim into a state of often violent agitation, before coma and death. Sometimes, in an aggressive delirium, even infected humans will bite – enabling the virus to find its way into a new host. While successful transmission from humans this way is rare, biting is the normal way the virus finds new victims in species such as dogs and bats.

Syphilis, caused by the spiral bacteria Treponema pallidum, can also dement its victims. It is thought to have pillaged many a famous – and infamous – mind: Toulouse-Lautrec, Friedrich Nietzsche and Al Capone to name a few.

These notorious diseases show the extremes of what bugs can do to our brains. However, we’ve come to know these enemies and to learn how to protect ourselves. We avoid rabid dogs and guard against catching syphilis.

But what’s become a new and pressing concern are bugs that we never suspected of tampering with our brains. While our genes play a major role in determining whether we will suffer from mental illness, so too do environmental factors, which so far remain poorly understood. When it comes to bugs that make us mad, “we are still at the frontier”, says Bruce Rothschild, a professor of medicine specialising in the evolution of syphilis at the University of Kansas.

Tanya Cooper

Your pet cat may be to blame for spreading some of these mind-altering bugs. Toxoplasma gondii is a parasite that loves felines because theirs is the only species that allows them to sexually reproduce. To go forth and multiply, T. gondii burrows into the gut of the cat and begins planning for the next generation by finding a way to travel to the next feline. Unlike rabies, it does not goad felines to bite each other, but instead makes use of a middleman – a hapless rodent.

The parasite’s eggs are excreted in cat faeces, where they dry and can become airborne. When a thirsty mouse drinks infected waters, the parasite wiggles into its brain and messes with its normally cautious behaviour. The mouse becomes generally reckless and replaces its hard-wired horror of cat urine with a liking for the smell. Like the crazy snails, it becomes easy prey. If all goes according to plan, soon T. gondii ends up in another cat. “For Toxoplasma gondii, the world is divided into cats and non-cats,” says Robert Yolken, a neurovirologist at Johns Hopkins University in Baltimore.

But occasionally the plan fails and the parasite infects another life form – the cat’s human servant, perhaps, after changing the litter box or drinking contaminated water. While estimates vary wildly, it’s believed that around a third of the world’s human population is infected.

Once inside a human, T. gondii can’t sexually reproduce – and since we are unlikely to be eaten by a cat, the parasite is at a loss. It doesn’t know this, however, and so journeys on to the brain just as it does in rodents. “T. gondii moves through our intestinal tract and goes into the blood, where it can penetrate the blood–brain barrier,” says Yolken. The parasite transforms into its latent form, and there it will stay. “It was not thought to cause problems until recently,” he says.

T. gondii was only considered to be an issue for those with weak immune systems, such as HIV patients and infants. But recent findings sound some alarm bells. Perhaps it’s not just the brains of rodents that T. gondii is tampering with. Certainly, there are no reported cases of cat owners suddenly professing a liking for the smell of cat urine. But some studies are finding a link between T. gondii infection and schizophrenia. A 2007 meta-analysis conducted by Yolken and published in Schizophrenia Bulletin calculated that infected individuals are almost three times as likely to have schizophrenia as the uninfected.

But Mathew Martin-Iverson, a professor of psychiatry at the University of Western Australia, says we need to be careful when interpreting these results. While acknowledging that infections could play a role in some mental disease, he warns that this particular association could be explained away by “other factors”. Poorer hygiene in schizophrenics, coincidental genetic vulnerability to both schizophrenia and infection, or even the fact that schizophrenics are more likely to smoke – which increases the frequency of hands moving to the mouth – might be the real reasons for the higher rates of infection.

But Yolken notes that with so little known about the disease progression of schizophrenia and other mental illnesses it’s too early to block anything out. “We’re at a stage where there are more questions than answers,” he says.

There is a growing list of bugs under suspicion for being linked to diseases of the mind. For example, in 1998, Susan Swedo at the National Institutes of Health in Bethesda, Maryland first reported in the American Journal of Psychiatry that 50 children developed symptoms strikingly similar to acute obsessive compulsive disorder (OCD) after being infected with streptococcus.

And this year a team at Taipei Veterans General Hospital published a study in Psychosomatic Medicine showing that infection with Varicella-zoster, the virus responsible for chickenpox and shingles, increases the risk of depression. The Taiwanese group followed 1,888 shingles patients with no psychiatric histories for a decade and compared their incidence of depression with uninfected controls. Patients with shingles had a slightly higher, but statistically significant, chance of developing major depression (2.2% versus 1.4%) than the control group.

To make a convincing case, however, and completely rule out “other factors” Yolken and his supporters must show how the bugs are manipulating our minds.

Tanya Cooper

There are two theories. One proposes that parasites deliberately sneak into our brains to manipulate them. The other suggests the bugs’ presence in our bodies triggers an overzealous inflammatory response that causes collateral damage to our brain tissue.

Either way, this sort of thing wasn’t supposed to happen. The brain was thought to be protected by the membranous blood–brain barrier. “The doctrine is that the blood–brain barrier protects the brain from agents that may harm it,” says Vaughan Carr, a professor of psychiatry at the University of New South Wales in Sydney. “But there are areas where the barrier is vulnerable.”

T. gondii provides the best evidence that a microbe might wield its power through direct manipulation after penetrating this barrier, rather than merely a hyperactive inflammatory response. In 2011, Glenn McConkey and his colleagues at the University of Leeds discovered it could specifically trigger the release of the chemical dopamine inside the brain cells of mice. Dopamine plays an important role in rewarding the behaviour of mice and men alike, giving the parasite power to change how we act.

The parasite may even have a double-punch mechanism. In 2012, a paper by Antonio Barragan at the Karolinska Institute in Stockholm, published in PLOS Pathogens, found that the parasite can flick a switch inside white blood cells forcing them to produce GABA, one of the brain’s chemical messengers that tones down the activity of brain circuits, particularly those involved with fear and anxiety. Valium, for instance, works in a similar way by activating and binding to GABA receptors. This could be one more arrow in the parasite’s quiver.

But Carr isn’t convinced. Even for T. gondii he argues that it’s not the direct work of parasites but the body’s frantic inflammatory response to them that has the main influence on our minds. “The growing body of evidence suggests that the body’s immune response, not the specific parasite, is what damages the brain,” he says.

According to Carr, the havoc is triggered when our immune system is alerted to a germ and unleashes a fury of inflammatory cells. Despite being released to destroy the bugs, some of these inflammatory cells seep through the blood–brain barrier and destroy brain cells as collateral damage. Since brain cells don’t regenerate very well, the damage can be disastrous.

Fingers are also being pointed at cytokines for causing much of the damage. These are the proteins that mobilise an inflammatory attack on microbial invaders. They are also responsible for so called “sickness behaviour” – the appetite loss, fatigue and general crabby feeling we get before a full-blown flu infection. Since these symptoms cross over quite remarkably with those of depression, researchers like Charles L. Raison at the Emory University School of Medicine in Atlanta blame hyperactive cytokines for causing some bouts of depression.

In 2006, he wrote a paper entitled “Cytokines sing the blues”, where he argued that a flood of cytokines could “access the brain via leaky regions in the blood–brain barrier” and alter the breakdown of chemicals such as dopamine and serotonin which are essential to regulating emotion. His evidence came from a series of animal experiments as well as from studies reporting that when cancer patients are given the synthetic cytokine IFN-alpha, a drug to boost their immune systems, rates of depression skyrocket. Depending on the dose used, 30% to 50% of patients on the cytokine drug suffer from depression.

Cytokines are not the only possible immune agent causing collateral damage in the brain. Another possibility, says Carr, is that the infection incites an autoimmune reaction in susceptible individuals. “These infections may trigger an autoimmune process in a genetically vulnerable person, where somebody produces antibodies against their own tissue, potentially including brain tissue,” he says. It’s this mechanism that is thought to be at play in children who suffer OCD-like symptoms after streptococcus infection. In 2004, Gavin Giovannoni, now a professor of neurology at the London School of Medicine and Dentistry, found that more than 90% of these children had antibodies that could latch on to the basal ganglia, a loop in the middle of the brain that controls fine motor movements, thinking and emotion. Reporting in the Archives of Disease in Childhood, Giovannoni suggested that the antibodies may have been recruited to kill the bacteria, but crossed the blood–brain barrier inflaming the basal ganglia.

So we have a spectrum. At one extreme, malevolent bugs like rabies have evolved to manipulate the aggression of mammals including us. Somewhere in the middle it looks like T. gondii evolved to make rats delusional but inadvertently may tip humans toward schizophrenia. Then there are the bugs that don’t manipulate human behaviour as part of any grand scheme, but only change behaviours as collateral damage. And while many people get infections without mental consequences, Carr suggests that those with genetic vulnerabilities to hyperactive immune responses may be most susceptible to brain harm by bugs.

Tanya Cooper

Despite the complexities surrounding these questions there has been at least one aspect that has seemed relatively straightforward – that all the bugs we’ve been looking at are invaders. Since 2012, however, the picture has become diabolically more complex. That year researchers around the world finished the first phase of the human microbiome project – creating an inventory of the bugs that inhabit the various niches of the human body. The vast majority of these microbes had been invisible to science because they are difficult to grow in a culture dish, but the microbiome project captures them via their DNA. It turns out there are around 100 trillion microbes in every human body, outnumbering human cells by 10 to one. Merely storing their genetic material in a database takes more than 14 terabytes.

These bugs are generally friendly, performing invaluable duties – they help digest our food, manufacture vitamins, temper our immune systems, prevent allergies, and overall play such a key role in orchestrating our metabolisms that they appear to be able to control obesity. Consider the famous study where poo transplants from thin humans transformed obese mice into thin mice.

Each person’s microbiome is different and the latest research is all about correlating particular types of microbiome with health and disease.

So what might microbiomes mean for mental health? In a paper published last year in Trends in Neurosciences, Jane Foster and Karen-Anne Neufeld at McMaster University in Canada proposed that some kinds of gut bugs could increase our risk of disorders such as anxiety and depression. After infection with Citrobacter rodentium, mice became more anxious compared to control mice, while rodents fed a blend of friendly bugs, called probiotics, saw that anxiety reduced.

Early studies in humans support the mouse findings. There are already reports that the probiotics Lactobacillus helveticus and Bifidobacterium longum have anti-depressive effects on people. And in a pilot study conducted by A. Venket Rao at the University of Toronto and published in Gut Pathogens, patients with chronic fatigue syndrome who received Lactobacillus casei daily for two months showed significantly less anxiety than those given a placebo.

Foster and Neufield argue that bacteria in the gut could influence our minds via the massive vagus nerve that connects our brains and guts. When mice are infected with the food-borne bacterium C. rodentium brain cells are triggered by the vagal nerve.

There are even tantalising – albeit largely anecdotal – hints that the gut microbiome may play a role in autism spectrum disorders (ASD). Around 90% of children with ASD experience some type of feeding problem, which is likely to have an effect on their overall gut health. Studies of faecal DNA extracts suggest that children with ASD have different gut bugs from children without the disorder. Earlier this year, in a paper published in Biomarkers in Medicine, Manya Angley and Lv Wang at the University of South Australia called for long term clinical trials to test whether probiotics can improve the symptoms of ASD.

Not surprisingly the sudden shifting of paradigms has left the medical community up in the air. If some bugs are good for mental health, others are clearly bad. It will be up to the next generation of researchers to understand which bugs are troublesome and how much of our mental health depends on stopping them getting inside our heads.

Also in Cosmos: Wasps turn ladybirds into zombies

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Wendy Zukerman is a science journalist based in Sydney.
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