Nali 1

Depressed with the news and in need of a good distraction, I headed down to the local animal shelter “just to look.” Famous last words. The next day, Nali, a nine-week old spayed female, fresh off the operating table, joined our household. My husband Ben had one condition for our new addition, that I handle the litter box. Sure, sure, I said. Small price to pay. 

As the designated scooper, it has become my job to fill the dreaded box. Fortunately the choices in litter available today promise to all but clean the box. These are all-natural, clumpable, disposable, flushable, odor-absorbing, biodegradable, and almost-good-enough-to-eat litters (our dog Ella can attest to this last one.)  Yet as helpful and harmless as the products available today may be, there is one thing they can’t promise: to lock-away Toxoplasmosis gondii. The parasite is a particular risk to those who are immunocompromised or pregnant. The last time I worried about this was two cats ago when our daughter was born. (This was, by the way, also probably the last time my husband ever scooped.) Now, twenty-two years later, our daughter Sophie is the one writing about T. gondii. Below is her essay and it turns out that T. gondii is more fascinating and more insidious than we could ever have imagined back in the day. It may also explain a bit about some human behaviors. Enjoy.

Parasite Mind Control: how a single celled parasite carried in the cat intestine may be quietly tweaking our behavior

By SOPHIE LETCHER

On November 30th, 2012, Jonah Evans* fell from a 30-foot ledge in Rock Bridge Memorial State Park, landing in a bed of leaves at the foot of a cave called “Devil’s Icebox.” The Missouri native teen was hiking with a friend when he got carried away jumping from rock to rock along the trail – ultimately leading to the disastrous accidental slip. Jonah was airlifted to the local hospital and made a full recovery, but this kind of behavior was not unusual. Jonah is an extremely intelligent, thoughtful, and kind hearted person, but as his mother, Emily*, attested after the accident, he tends to put himself in reckless situations – jumping atop slippery rocks along a ledge perhaps the most devastating example. As mothers do in these situations, Emily searched for some way that she was at fault for Jonah’s fall.

Sitting around a table of friends discussing the horrific accident (post recovery), Emily mulled over why Jonah could be so reckless when he’s generally such a clear-headed person. “I did spend a lot of time around cats when I was pregnant with Jonah – maybe he contracted that parasite that makes you crazy,” she half-joked. The parasite Emily was referring to is called Toxoplasma gondii (T. gondii, for short), and it was around this time that pop science was picking up the idea that many cats carry a mind-altering parasite (T. gondii) that can infect humans and manipulate them into illogical risk taking behavior.1 Although the idea seems like science fiction, mounting evidence suggests that Emily may have been onto something. While she isn’t at fault for Jonah’s fall, infection with T. gondii may very well change one’s behavior –  uncharacteristic recklessness being just the tip of the iceberg.

*Names have been changed to protect privacy

WHAT IS TOXOPLASMA GONDII?

T. gondii has been on a list of major pathogenic parasites since the 1920s2 but until fairly recently, knowledge of the effects of infection on humans halted after the initial stage of infection. Acute toxoplasmosis, infection with rapidly dividing T. gondii, is usually asymptomatic in healthy humans, sometimes causing mild flu symptoms such as swollen lymph nodes, muscle aches, or fatigue.3 However, when the immune system is unable to quell the rapidly dividing invaders, as is the case with the immunocompromised (such as people who are HIV positive), infection can lead to severe fever, nausea, confusion, headaches, or seizures; potentially life-threatening situations.3 Acute toxoplasmosis is also a risk factor if acquired while pregnant.

As the host’s immune system starts to halt rapid division of T. gondii, the parasite switches gears and barricades itself in intracellular cysts that are safe from the host’s immune response.  It remains inside these cysts, slowly dividing, throughout the host’s lifetime.4 Parasite-filled cysts can be found in all types of host tissue, but seem to have a higher affinity for neural and muscular tissue.4 Though this slowly dividing stage was initially thought to be asymptomatic, evidence now suggests that the parasite may be quietly tweaking our behavior and underlying some of the most devastating neurological diseases. 

T. GONDII LIFE CYCLE: FROM CATS TO RATS AND BACK

T. gondii Life Cycle - Page 1 (1)To understand these parasite induced behavioral changes in humans, it is important to understand why T. gondii may have evolved the ability to change host behavior – and the parasite’s complex life cycle is at the root of it. T. gondii can only reproduce inside the cat intestine – but because sexual reproduction is slow and costly, the parasite outsources itself to an intermediate host where it can asexually reproduce. Dormant forms of the parasite leave the cat through its feces and are ingested by other mammals (the intermediate hosts). During this period of the life cycle, T. gondii divides rapidly, proliferating for as long as it can until ultimately returning to the cat intestine to sexually reproduce again and complete its life cycle. How does the parasite find its way back to the cat intestine? Although it is able to infect any warm-blooded mammal, it makes the most sense for T. gondii to infect mammals that will be eaten by cats – and this is where it gets interesting. When T. gondii is ingested by rodents (common cat prey), the parasite manipulates the rodent’s behavior in a way that makes them easier prey for cats; Infected rodents experience “fatal feline attraction”5,6 where they lose their innate fear of cats, spend more time in vulnerable positions,5 and are even sexually attracted to cat urine.7

So what does this have to do with humans? As mentioned before, once T. gondii is shed from the cat in its feces, any warm-blooded mammal is susceptible to infection – and it turns out that humans can contract the parasite through many means, leading to a 30-70% infection rate worldwide.8,9 The life cycle of T. gondii is summarized in Figure 1, including possible routes of transmission to humans. It seems as though the behavioral manipulation that T. gondii induces in rodents to facilitate its life cycle may go slightly haywire when the parasite finds its way into human tissue.

FROM CATS TO…HUMANS?

From T. gondii’s perspective, infection in humans is a dead end – unless we have really powerful, sadistic pet cats or find ourselves in the presence of a hungry lion it is unlikely that we will be eaten by a cat and thus return T. gondii to the cat intestine. Nonetheless, the manipulative parasite still finds its way into a large proportion of the human steakpopulation. Although cats play a pivotal role in T. gondii’s life cycle, most of the transmission to humans happens through consuming undercooked contaminated meat, contaminated water, or eating unwashed vegetables.3 A study done in 2002 found that 38% of British commercial meat was contaminated with T. gondii,8 and countries such as France that prefer meat undercooked have a higher rate of infection.9 Unwashed vegetables carry the parasite when grown in dirt with cat feces containing T. gondii, and parasite-laden feces also find their way into water supplies.3 Lucky for cat lovers, it seems as though domestic cats have a very low chance of carrying the parasite, negating the T. gondii-based “crazy cat lady” theory.1

STRANGE BEHAVIORAL CHANGES

The acute symptoms of T. gondii infection are easily digestible – the fact that single-celled organisms such as viruses and bacteria can bring us physical harm is accepted and understood. The behavioral changes, however, are far more complex and as such much more terrifying. As humans are “accidental hosts,” it seems as though the behavioral changes are spin-offs of the manipulation seen in rodents to make them easier prey for cats.

sex differencesOne of the pioneer studies in uncovering behavioral changes in humans with chronic T. gondii infection was done by a Czech scientist named Jaroslav Flegr, who wanted to see if the reckless behavior observed in infected rodents translates to humans. Indeed it seems to – Flegr found that a potential combination of reckless behavior and decreased reaction time in infected individuals lead to a greater likelihood of getting in a car accident. More specifically, infected individuals are 2.65 times more likely to be in a risky crash, an odds ratio that may contribute to up to one million car crash-related deaths per year.10 Crazy as it sounds, this study has been replicated in other countries and the theory holds in context of further studies on T. gondii induced behavioral changes.11

Interestingly, many T. gondii-induced changes seem sex-specific, as summarized in Figure 2. One of the most fascinating differences is that while men seem to retain the “fatal feline attraction” seen in infected rodents – perceiving the smell of cat urine as more pleasant compared with uninfected controls – infected women are the opposite, finding cat urine less appealing than uninfected controls.12 Though there hasn’t been an explanation for this sex-specific difference in odor perception yet, some of the other differences may be explained by the fact that T. gondii infection leads to increased testosterone (the male sex hormone) in males but not in females. Many scientists also speculate that differences occur simply because the male and female brains are wired differently, and thus may react to the parasite-induced neurological changes in different ways.13

What does appear to be conserved throughout infected humans regardless of sex is the correlation between seroprevalence (detection of immune response to T. gondii in the blood) and various neurological disorders. Numerous links have been made between infection and depression, suicides, personality changes, bipolar disorder, OCD, and, most prominently, schizophrenia.13 Recent studies have also found correlations between infection and epilepsy14 and certain types of cancers.15,16 Putting together all the indirect ways T. gondii infection could kill you, the parasite may be one of the most successful undercover assassins that most people have no idea exists!

HOW? PUTTING TOGETHER PIECES OF THE PUZZLE

How can a single-celled organism cause us to crash our car or even drive people to schizophrenia or suicide? Although there isn’t a single satisfying answer as to how T. gondii is able to elicit such complex and specific alterations in the minds of hosts, multiple lines of evidence are beginning to chip away at how the parasite changes host behavior.

Immune response

One of the primary explanations for T. gondii-induced behavioral changes in humans is the indirect effect of the immune system working to keep the parasite “dormant.” The constant production of chemicals needed to keep infected tissues safe from total destruction by the parasite are also involved in other essential processes. For example, the immune response leads to breakdown of a key precursor of serotonin, a “feel good” neurotransmitter that is often lacking in the brains of those with depression.17 Constant activation of the immune response also messes with the glutamate pathway, a neurotransmitter involved with anxiety.17

Parasite localization

Another plausible way that T. gondii manipulates hosts is simply through residing in the right areas of the brain. The brain is an extremely complex organ, and disrupting proper functioning of a specific place may be enough to elicit a specific behavior. Cysts seem to preferentially form in areas of brain associated with emotions, fear, and odor processing (olfactory bulbs, amygdala, and nucleus accumbens).17 Further, studies have indicated that rats only have “fatal feline attraction” and associated anxiety behaviors when the parasite is localized to certain areas of the brain involved with higher cognitive processes.18  However, because most physical and cognitive functions of the host are left intact, it seems unlikely that behavioral changes are solely due to T. gondii localization. It is more likely (and perhaps more terrifying) that the parasite manipulates specific cells and neural circuits in just the right way where behavior is altered but physically the host is unchanged.

Neurotransmitter modulation

Neurotransmitters are the chemical messengers of the brain, running the show of emotions, actions, and everything in between. One of the most studied and most accepted neurological changes in the brains of T. gondii infected animals – rodents and humans alike – is the increase of host dopamine levels.19,20 Dopamine is a neurotransmitter involved in the reward pathway and motor control,21 and increased levels of dopamine relate to many of the observed behavioral changes, from movement issues to hyperactivity to schizophrenia. Although the mechanism by which T. gondii changes host dopamine levels isn’t clear, genomic analysis has revealed that the parasite may synthesize proteins that are critical in the production of dopamine.22 These studies imply that T. gondii uses these proteins to speed up dopamine production inside infected brain tissue, facilitating the increased global dopamine levels that alter behavior.

T. GONDII AND SCHIZOPHRENIA

Schizophrenia affects about 1% of the population and is one of the least understood mental illnesses, mystifying neuroscientists for ages.23 Symptoms of schizophrenia vary, but generally include hallucinations, disordered thoughts, and losing touch with reality.23 Strangely enough, T. gondii infection is the greatest risk factor for developing the disease, bypassing genetic and environmental factors.24 Patients with schizophrenia have a higher prevalence of T. gondii infection across a range of meta-analyses,25 and some rare cases of acute toxoplasmosis have been documented with symptoms that are very similar to schizophrenia – auditory hallucinations, thought disorders, blunted affect, etc.24 These cases are especially prevalent in infected immunocompromised individuals, where T. gondii has free reign of host tissues.24 Scientists speculate that infection may switch on predispositions for developing schizophrenia – meaning that T. gondii infection doesn’t directly cause schizophrenia, but if genes, brain structure, or environmental conditions make one more susceptible to the disease, T. gondii may simply flip the switch that effectively “turns on” the disease.

So how does T. gondii flip this switch? A hallmark of a schizophrenic brain and likely the underlying cause of many behavioral deficits is an increase in neural concentrations of dopamine – and as discussed before, increasing host dopamine levels also seems to be T. gondii’s forte.20 Interestingly, antipsychotic drugs used to treat symptoms of schizophrenia that target the dopamine system (haloperidol, valproic acid) also seem to inhibit T. gondii replication and ability to get into the brain, harboring the idea that antipsychotics may be at least partially effective as antiparasitics.26 Another interesting connection is that many schizophrenic patients experience deficiencies in their olfactory systems – if T. gondii is a causative factor for schizophrenia, this could be explained by the olfactory manipulation involved with “fatal feline attraction.”12,27 Though the connection between T. gondii and schizophrenia is still fairly recent and not well understood, it creates exciting opportunities for the generation of novel therapeutics for one of the world’s most devastating neurological diseases.

LIKE THE SMELL OF CAT PEE?

like the smellOne of the most fascinating manipulations that occurs in rodents and seems to be (at least partially) conserved in humans is the selective change in the perception of cat odor. The olfactory system is one of the most intriguing and complex sense systems – each “scent” (chemical) has a specific wiring and a specific receptor that tells the brain what scent was picked up. Webster and McConkey (2010) speculate that T. gondii may specifically trip the wiring for the “cat odor” pathway and make the host no longer perceive cat odor. Thus, if a cat is stalking an infected rodent, the rodent will not sense the cat approaching and will make for extremely easy prey. Alternatively, the parasite may target the innate pathway in the olfactory system – the wiring that rodents are born with that sends alarms to the fear response pathway when predator odors are sensed.17 Further, this fear pathway may be rewired in a way that ties it together with the sexual arousal pathway – meaning that when rodents sense something that they should fear (cat odor), instead they feel sexually aroused. Interestingly, this specific rewiring of fear and sexual arousal also appears to be conserved in humans. One study of 36,564 participants found that those infected with T. gondii (both men and women) have increased attraction to sexual masochism and BDSM-related practices.28 While this behavioral manipulation does not have to do with odor detection, it may be another example of a human spin-off of rodent targeted T.gondii induced changes.

WHAT DOES THIS MEAN FOR YOU? IS THERE A CURE?

Because the behavioral changes associated with chronic T. gondii infection are not well understood, there isn’t a specific cure for targeting chronic infection – and as discussed, the encysted form of the parasite that occurs with chronic infection is extremely difficult to target and out of reach from antibiotics or other typical antiparasitic drugs. The most effective combat against infection is prevention: fully washing vegetables before eating, ensuring meat is fully cooked, and being careful around outdoor/stray cats.

If you’re like me, learning all this information will  immediately make you question if we actually make any of our own decisions, or are simply a puppet of the parasites residing in our brains. Even scarier, T. gondii is just one of the millions of organisms we host in our bodies – where do our thoughts and desires end and microorganisms’ begin, and how can we tell the difference between the two? For now, we may as well accept the fact that we are not alone in our bodies – and next time you do something reckless, just blame the T. gondii!

Works Cited

  1. McAuliffe, K. How Your Cat Is Making You Crazy. The Atlantic (2012).
  2. Innes, E. A. A Brief History and Overview of Toxoplasma gondii. Zoonoses Public Health 57, 1–7 (2010).
  3. CDC-Centers for Disease Control & Prevention. CDC – Toxoplasmosis – General Information – Pregnant Women. (2010).
  4. Dubey, J. P., Lindsay, D. S. & Speer, C. A. Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin. Microbiol. Rev. 11, 267–299 (1998).
  5. Berdoy, M., Webster, J. P. & Macdonald, D. W. Fatal attraction in rats infected with Toxoplasma gondii. Proceedings of the Royal Society B: Biological Sciences 267, 1591–1594 (2000).
  6. Vyas, A., Kim, S.-K. & Sapolsky, R. M. The effects of toxoplasma infection on rodent behavior are dependent on dose of the stimulus. Neuroscience 148, 342–348 (2007).
  7. House, P. K., Vyas, A. & Sapolsky, R. Predator cat odors activate sexual arousal pathways in brains of Toxoplasma gondii infected rats. PLoS One 6, e23277 (2011).
  8. Aspinall, T. V., Marlee, D., Hyde, J. E. & Sims, P. F. G. Prevalence of Toxoplasma gondii in commercial meat products as monitored by polymerase chain reaction–food for thought? Int. J. Parasitol. 32, 1193–1199 (2002).
  9. Fromont, E. G., Riche, B. & Rabilloud, M. Toxoplasma seroprevalence in a rural population in France: detection of a household effect. BMC Infect. Dis. 9, 76 (2009).
  10. Flegr, J., Havlícek, J., Kodym, P., Malý, M. & Smahel, Z. Increased risk of traffic accidents in subjects with latent toxoplasmosis: a retrospective case-control study. BMC Infect. Dis. 2, 11 (2002).
  11. Yereli, K., Balcioğlu, I. C. & Ozbilgin, A. Is Toxoplasma gondii a potential risk for traffic accidents in Turkey? Forensic Sci. Int. 163, 34–37 (2006).
  12. Flegr, J., Lenochová, P., Hodný, Z. & Vondrová, M. Fatal attraction phenomenon in humans: cat odour attractiveness increased for toxoplasma-infected men while decreased for infected women. PLoS Negl. Trop. Dis. 5, e1389 (2011).
  13. Flegr – Schizophrenia bulletin, J. & 2007. Effects of Toxoplasma on human behavior. academic.oup.com (2007).
  14. Palmer, B. S. Meta-analysis of three case controlled studies and an ecological study into the link between cryptogenic epilepsy and chronic toxoplasmosis infection. Seizure 16, 657–663 (2007).
  15. Yuan, Z. et al. Toxoplasma gondii antibodies in cancer patients. Cancer Lett. 254, 71–74 (2007).
  16. Thomas, F. et al. Incidence of adult brain cancers is higher in countries where the protozoan parasite Toxoplasma gondii is common. Biol. Lett. 8, 101–103 (2012).
  17. Webster, J. P. & McConkey, G. A. Toxoplasma gondii-altered host behaviour: clues as to mechanism of action. Folia Parasitol. 57, 95–104 (2010).
  18. Evans, A. K., Strassmann, P. S., Lee, I.-P. & Sapolsky, R. M. Patterns of Toxoplasma gondii cyst distribution in the forebrain associate with individual variation in predator odor avoidance and anxiety-related behavior in male Long–Evans rats. Brain Behav. Immun. 37, 122–133 (2014).
  19. Prandovszky, E. et al. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism. PLoS One 6, e23866 (2011).
  20. Skallova, A., Kodym, P., Frynta, D., Flegr – Parasitology, J. & 2006. The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an ethological and ethopharmacological study. cambridge.org (2006).
  21. Howes, O. D. & Kapur, S. The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway. Schizophr. Bull. 35, 549–562 (2009).
  22. Gaskell, E. A., Smith, J. E., Pinney, J. W., Westhead, D. R. & McConkey, G. A. A unique dual activity amino acid hydroxylase in Toxoplasma gondii. PLoS One 4, e4801 (2009).
  23. Picchioni, M. M. & Murray, R. M. Schizophrenia. BMJ 335, 91–95 (2007).
  24. E. Fuller Torrey & Robert H. Yolken. Toxoplasma gondii and Schizophrenia. Emerging Infectious Disease journal 9, 1375 (2003).
  25. Sorlozano-Puerto, A. & Gutierrez-Fernandez, J. Toxoplasma gondii and Schizophrenia: A Relationship That Is Not Ruled Out. in Schizophrenia Treatment – The New Facets (ed. Shen, Y.-C.) (InTech, 2016).
  26. Jones-Brando, L., Torrey, E. F. & Yolken, R. Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr. Res. 62, 237–244 (2003).
  27. Cohen, A. S., Brown, L. A. & Auster, T. L. Olfaction, ‘olfiction,’ and the schizophrenia-spectrum: an updated meta-analysis on identification and acuity. Schizophr. Res. 135, 152–157 (2012).
  28. Flegr, J. Does Toxoplasma infection increase sexual masochism and submissiveness? Yes and no. Commun. Integr. Biol. e1303590 (2017).

29. Kramer, P. & Bressan, P. Humans as Superorganisms: How Microbes, Viruses, Imprinted Genes, and Other Selfish Entities Shape Our Behavior. (2017). doi:10.17605/OSF.IO/K39M

Advertisements