Little trouble makers

Welcome to 2019: the time of sophisticated technology like never before. Your handheld computer resting in your pocket, your light-weighted laptop, your magical Bluetooth device, your orchestral MP3 player and your seemingly limitless option of movies on your smart TV are all a product of technological innovations for pleasure. Technological advances have also carried over into medical applications, nearly turning science fiction to science fact. A thrilling theme in popular Sci-Fi culture has always been the concern that mind control would emerge out of this technological transition. Although, what if mind control was independent from technology altogether and around far longer than any human? If we were being controlled for instance—how would we even know?

Don’t Bug me

I realize that some microscopic bug festering in a puddle knows more about the brain than all of us neuroscientists combined.

-Prof. Robert Sapolsky

Over thousands and thousands of years the wonders of biology have created organisms that thrive on what we may refer to as mind control. Parasites are organisms that live inside a host to survive at the expense of the host. For sake of discussion, no, this is not a discussion about your flatmate. Rather, I want to talk about the parasites in biology that are masters of puppeteering their victims.

An interesting example is a fungus called Cordyceps that ensures its’ survival by emitting parasitic spores for those stupid organisms that accidently ingest it. Over plenty of years, fire ants have become a rival of this parasitoid (and for good reason). If a fire ant ingests this material, it will uncontrollably travel to the top of a nearby plant and latch its mandible onto a supportive leaf. As graphic as it may seem, the spore will continue to develop by deriving the internal resources from the ant. The plant-like fungus surfaces from the now deceased ant and the lifecycle of the fungus eventually completes. Evolutionarily, it is advantageous to radiate spores from an aerial position to cover a larger area of infectious ground below. The fungi happily grow only to await the next round of ant to fall for their clever trick.

A popular example of mind control is the rabies virus. Following a wound (usually a bite), Rabies enters the periphery of nerves and navigates its way to the central nervous system of a host. Once in the brain, it can stall neurochemical transmission, disturb ion channel activity and down-regulate gene expressions which are all crucial for normal cell functioning. Hijacking brain chemistry is what leads to the onset of aggression behavior and is a clever way of ensuring your host chomps onto another for further transmission. It’s worth mentioning that rabies manages to complete operation takeover without causing cell decay, hemorrhages (bleeding) or triggering an immune response; or in other words, “setting off any alarms.”

Leucochloridium paradoxum or a green-banded broodsac is a type of parasitic flatworm that makes its way into the eye stalks of snails residing on leaves. The flatworm lures the snail to enter well-lit areas and pulsates in the eyestalks to mimic the appearance of a tasty caterpillar to a bird’s eye above. The snail becomes lunch for a keen-eyed bird passing by and later expels the waste (and newly formed larvae) nearby to allow the next generation of snails to restart the process. Creeped out yet?

Parasites can even form an alliance with viruses on operation takeover. A parasitic mite called Varroa destructor can act as a vector or vehicle for the deformed wing virus to infect honeybees. Upon infection, the virus suppresses the immune system and regulatory cellular activity of the honeybee, enabling the mites to flourish with reproduction. The mite and virus grow happily together as they destroy the life out of the bee.

Interestingly, the parasitic cells often manage to impact specific areas of the body. That is, there isn’t a gross destruction of tissue, rather the hijacking appears almost calculated. You must take my word for it that I have barely even mentioned a fraction of all the known examples in biology. I ponder whether this is more fascinating or terrifying. Nevertheless, parasites are certainly amongst us—but what does any of this have to do with humans?

Miniscule Manipulative Monsters

The parasite I wanted to discuss is one called Toxoplasma Gondii (or simply, Toxo). It is a protozoan parasite that infects a third of the world’s population. Parasitic cysts are spread by ingesting raw/undercooked meats, or contaminated food/water often from fecal matter from cats. This should be attention-grabbing since approximately 8 million Brits own cats as house pets. After infection, parasitic cysts reside in the nervous system and muscle.  Given the sheer magnitude of this successful spread, it is certainly a good thing that Toxo remains asymptomatic to most adults. Though, experiencing symptoms of Toxoplasmosis (infection) is more common during pregnancy (with harmful effects to the fetus), those with ocular disease and/or immunocompromised individuals. However, a mounting amount of literature has Toxo playing all sorts of games with nervous systems.

Toxo has become somewhat of a meme on the internet and a popular example in biology textbooks due to its fascinating ability to modify neural functioning in rats. For the sake of explanation, let’s start Toxo’s journey is inside a house cat who later expels the parasite within its fecal matter. At first, Toxo is in trouble because it had left a preferable environment for reproduction by being inside the gut of the cat. Not to worry for Toxo, because rats are always caught up in filth and are likely to acquire it. Isn’t it weird to say a parasite figured out how to hitchhike?

Once in the system of a rat (namely the brain), Toxo will actively destroy the innate ability of the rat to fear cat odors such as urine [7]. In doing so, rats will become more susceptible to encounter another cat, be eaten and thus find its way back inside the cat to restart the cycle. Even more startling, Toxo has been able to rewire the sexual reward signals in a subtype of rat to cause cat pheromones to not smell aversive, but pleasurable. Toxo can also make infected rats appear more attractive to one another and increase their mating behaviors. This leads to the lateral transmission of Toxo to more rats; more rats equals more chance to meet a cat.

The plot in each one of these scenarios is the induction of some sort of behavioral change to act in a favorable manner for the interlopers. An interesting study in 2006 highlights this behavioural change. Researchers investigated whether an antipsychotic drug (haloperidol), mood-stabilizing drug (valproic acid) and an anti-bacterial drug (pyrimethamine with dapsone) could yield behavioral/cognitive effects on a Toxo-infected rat model. Rats were placed in an environment with distinct odors in each corner (cat urine, rat urine, non-predator urine (rabbit) and neutral odor (water)) on a bed of wood chips. Food and drink marked each corner and attraction to feline urine & behavior were then measured. The untreated infected groups spent significantly more time in the ‘cat corner’ and were significantly more likely to remain still, groom and drink water compared to their uninfected counterparts. Treated groups of both pyrimethamine with dapsone and haloperidol (but not valproic acid) yielded a significant reduction in feline attraction and predation-risk behavioral traits. In other words, a reduction in Toxo (treated) meant a reduction in unwanted behaviors. The illustration below perhaps is the story through a rodents’ eyes.

Toxo can exert the same effects on Chimpanzees (our closest relative) by inhibiting the innate aversion to the smell of leopard urine. Again, what about humans? Despite most infections remaining subclinical, Toxo’s induction of proteins to suppress immune detection have been shown to alter behavior in humans, too.

For instance, a collection of 11 studies in the Czech Republic examined personality characteristics using Cattell’s 16-personality factor questionnaire on subjects who did or did not show the presence of Immunoglobulin G/M (IgG/IgM) antibodies for Toxo. These antibodies are critical to determine an active or inert infection. Interestingly, 9 out of 11 studies reviewed found significant psychometric differences. After compiling the results, infected men showed an increased likelihood to abandon rules and to be more suspicious, impulsive & dogmatic. Whereas infected women showed an increase in warm heartedness, extroversion, persistence & conscientiousness. The latter sounds like the intimacy changes in rodent mating behavior following infection.

Moreover, performance on psychomotor scores have also been noted. A study from 2001 noted significantly longer reaction times and a slightly reduced attention level in subjects with latent asymptomatic toxoplasmosis compared to controls without Toxo antibodies.

Curiously, a 2002 case-control study found subjects also with latent toxoplasmosis have a significantly higher chance of getting into a motor vehicle accident compared to non-infected individuals. This is in line with a Turkish study that found those involved in traffic accidents expressed IgG (24.7 per cent) and IgM (3.2 per cent) antibodies for Toxo indicative of either past or current infection. The rate of IgG and IgM antibodies for age-matched controls were 6.5 per cent and 0.5 per cent, respectively. Perhaps most startling, are the number of studies drawing a correlation between self-guided violence and suicidal behavior; perhaps explaining all the traffic accidents. Again, one can draw a parallel with the effect on rodents.

You may have predicted it already but, Toxo has been shown to be implicated in mood disorders such as bipolar disorder and psychosis. IgM antibodies to Toxo were significantly elevated in psychiatric patients in mania vs. healthy controls. IgG had no significant difference yet it’s worth mentioning that no other psychiatric patients showed elevated IgM to Toxo suggesting a unique mechanism underlying mania that Toxo figured out how to hijack.

Could this be the limit for these little monsters? No, according to the literature. First-episode schizophrenia patients have also demonstrated elevated levels IgG, IgM and IgA antibodies for Toxoplasma compared to matched subjects. Moreover, a 2017 review paper in the Journal of Advances in Clinical and Experimental Medicine found an abundance of Toxo infestations in individuals with psychiatric disorders, including schizophrenia. For good measure, 42 studies on schizophrenic patients from 1961-2006 have found higher rates of IgG antibodies for Toxo compared to psychiatrically healthy controls. Some literature suggests closer to 70 reports have been found.  

If the parasite can sneak into our nervous systems, push our buttons by altering personality, performances and behavior then there must be some change occurring in the brain. What may this mean for those who already possess dysfunctional & disorderly brain physiology as seen in neurodegenerative diseases?

Neurodegeneration

Neurodegenerative diseases are a class of neurological disease whereby there is a progressive loss of structure and/or function of brain cells resulting in cell death and permanent dysfunction. Unfortunately, there are few treatments let alone cures available for such sinister diseases. Neurodegenerative diseases account for a tremendous economic burden with an estimated 1 trillion-dollar cost in the United States for dementia alone. If you consider the global care for dementia to be a country, it would represent the eighteenth largest world economy; not to mention the psychological distress of caregivers, family and patients.

Toxo has shown to play a role in a common pathological process in neurodegeneration—excitotoxicity. Following the introduction of Toxo to murine models, a primary astrocytic glutamate transport (GLT-1) was significantly down-regulated in the prefrontal cortical areas (critical area for decision making, planning, emotion regulation, thought, memory) of the brain. In addition, other vital proteins that span the synapse have shown distinct changes upon Toxo infection. Consequently, an abundance of extracellular glutamate accumulates in synapses which is toxic to brain cells and triggers a process called apoptosis or programmed cell death.

Just as the mood disorders, patients with Alzheimer’s disease (a type of dementia) have significantly higher levels of Toxo antibodies compared to healthy controls. In addition, beta-amyloid, hyperphosphorylated tau (hallmarks of Alzheimer’s disease) death of olfactory brain cells and behavioral changes were all noted in mice infected with Toxo, although the sample size was low.

The vasculature of the brain also plays a critical role in brain health (especially critical for ill patients). In mice, Toxo has been shown to not only decrease cerebral blood flow only 10 days after infection but there was a reduction in the formation of new blood vessels and a decrease in the length of new vessels that did form. This is all accompanied with a heightened level of inflammation to add fuel to the fire.

Another neurodegenerative disease called Huntington’s Disease experience the effects of Toxo as well. Huntington’s mouse models infected with Toxo had a significantly less chance of survival compared to Huntington’s control mice and wildtype mice with the infection. Toxo essentially protects itself by degrading a protein called tryptophan via activating a catalyst protein. Coincidentally, the degradation of tryptophan is implicated in Huntington’s pathogenesis.

This data suggests that Toxo certainly has the capacity to influence neurodegenerative disease and could provide cause for physicians to adapt care accordingly.

Other Side of The Coin

However, there are always two sides to every coin. Some studies have run in opposition to indicate infection of Toxoplasma gondii can be protective to the nervous system. I suppose they reciprocate some good health after we continually store and feed little felines in our home.

Contrary to the results I just told you about, a substantial decrease in beta-amyloid plaques in Toxo-infected Alzheimer’s disease mouse models when compared to controls. A more recent study from 2016 had found similar results, whereby Toxo-infected Alzheimer’s models showed a reduced amount of beta-amyloid deposits in the cortex and hippocampus compared to non-infected mice. Non-infected mice with the same pathology were cognitively impaired compared to the relieved infected mice. An up-regulation of both monocytes and macrophages was also noted; a sort of janitorial service for the brain.

Additionally, Interferon-y is a primary cytokine released as a line of defense against a Toxoplasmosis that can activate these same janitorial cells such as microglia, astrocytes or macrophages. These cells can release toxic substances that cause inflammation to signal there has been a disturbance—Nitric Oxide (NO) is one of these substances. Therefore, upon Toxo entry you might expect more Interferon-y, leading to more microglia and thus more NO to cause inflammation. Except Toxo-infected microglia & astrocyte cells have been shown to decrease their NO production and release, leading to less inflammation and a more preserving environment for the brain. Not only can Toxo reduce inflammatory cytokines but it can also significantly increase anti-inflammatory cytokines.  

However, these results are limited to studies in animal models and should be treated with skepticism when making claims about Toxo in humans. With respect to neurological health, it is currently unknown whether 30 per cent of the population do receive some mutual benefit or whether the harmful effects take precedence.

Paying the Toxo Tax

It is true science has made leaps and bounds over the last century and it continues to design technology virtually unimaginable two generations ago. Yet, on a larger scale parasites had thousands of generations to study and develop a symbiotic relationship with organisms.

Now that we are fortunate enough to systematically study parasites, it’s clear that humans are not exempt from their trickery. Toxo has been clinically known to be a threat during pregnancy and immunodeficiency, but there is now an abundance of evidence linking Toxo infections with schizophrenia, mood disorders and behavioral changes. Perhaps this could offer insight into the nature of these ailments and create novel therapeutic approaches.

Furthermore, upon examining neurological literature there is a legitimate concern that Toxo may be able to exacerbate neurodegenerative processes. At the same time, some literature has paradoxically found the presence of Toxo to be neuroprotective from neurodegenerative disease. While the jury is still out, it is not far-fetched to suggest that Toxo plays a role in exacerbating (or inhibiting) pathological processes such as those found in neurodegeneration.

Having raised caution, it’s important to consider some faults with these findings. Firstly, this research is largely correlational. That is, few studies claim that Toxo is the cause of the dysfunction in question. Moreover, while the results are significant, the epidemiological data do not always align. For example, schizophrenia presents itself to approximately 0.28-0.4 per cent of the public, whereas at minimum we see a greater presence of Toxoplasmosis by a factor of 75. Thirdly, we are left with the challenging ‘chicken or the egg’ scenario; does Toxoplasma contribute to the onset of mania or do people in a state of mania better contract Toxoplasma gondii? Lastly, the removal of latent Toxo cysts have proved to be a difficult procedure. Either way, the capacity for this microscopic-being to have some impact on humans is undoubtable.

It is puzzling why there hasn’t been a greater effort to research the implications of parasitic infections thus far. Especially since Toxoplasma Gondii is so widely present on a global scale and many parasites have proved themselves to be clever neural engineers—twisting the tales of biology for their own happy ending.  

There is a strong case to be made that such a parasite like Toxo “understands” biology more than we ever will. Those with an interest in medicine should acknowledge the possibility of these little trouble makers to play their neurological tricks on not only barn-dwellers or our house pets—but on us, too.

This post was written by Matt Ball and edited by Karolina Zieba.