INTRODUCTION

It may be overly generous to say that the parasite toxoplasma gondii has not received much coverage in the popular press. In fact, discussion over this parasite is almost exclusively limited to scientific literature. As I have studied this topic I have frequently wondered why this is the case. By the end of reading this post you may wonder the same thing. To add some personal qualification in writing this topic I will say that I currently conduct epidemiological research at Brigham Young University investigating the long-term effects of latent toxoplasmosis (infection with toxoplasma gondii). I would not claim myself an expert on the topic since I am certainly no parasitologist. However, my studies have demanded extensive background research and have provided me with a good grasp of what this specific parasite is and is not capable of. As I’ve studied this little organism, I’ve been fascinated by the impact such a small creature could make. Toxoplasma gondii (T. gondii for short from now on) is an intracellular parasite that most often finds its home in the everyday house cat. Infection primarily occurs through ingestion of previously infected meats but may also be contracted via congenital transmission (mother to baby). Upon infection, the parasite is released into the bloodstream of its new host and is dispersed throughout the organism. The immune system is well capable of taking care of the foreign threat in all areas of the body except the brain. Once it has crossed the blood brain barrier, the parasite deposits itself inside the cells of the brain (neurons) and hides itself away. Initial infection is followed by cyst formation. These cysts allow the parasite to essentially build a shell around itself within the cell. Where normal intracellular immune responses should have been able to eliminate it, the miniature cyst built around the parasite protects it for the life of the host organism. As previously mentioned, the primary host for this organism is the cat. As a common household pet, it is near impossible for any human to live a single day without seeing a couple of roaming neighborhood cats. Due to the frequent contact between cats and humans it is natural to wonder if humans are common hosts for T. gondii as well. In fact, the worldwide prevalence rate of toxoplasmosis among humans is about 30% (Henriquez, 2009; Montoya, 2004). Yes, that means that just under 1 in every 3 humans have already been infected with this parasite. With such a high prevalence rate I feel that it is important for the general population to know about and understand this parasite and how it may affect their daily lives. Being that T. gondii most commonly calls the brain its home, I will discuss the ramifications of hosting such a parasite in an organ so important for normal day-to-day life. This includes changes in behavior, cognitive ability and local immunity.

BEHAVIOR

Though currently not declared the cause of any major psychological or neurological disorder, T. gondii has been associated with schizophrenia, bipolar disorder, parkinson’s disease and many others. The primary cause of this relationship is likely due to the parasites innate ability to produce copious amounts of dopamine, a common neurotransmitter found in the brain. Interestingly, not only can this parasite release dopamine, it has the capability of manufacturing it. Endowed with the cellular machinery to convert early materials into natural dopamine, each parasite is capable of producing enough of this neurotransmitter to fill intracellular cysts and virtually dominate a cell. Previous research has found a strong relationship between the levels of dopamine expressed in specific areas of the brain and disorders such as schizophrenia and parkinson’s disease. Elevated dopamine expression results in schizophrenia while the inverse is true for parkinson’s disease. Therefore, it is easy to see how T. gondii’s production of dopamine may be related to increased rates of schizophrenia. Infected in specific brain regions, T. gondii infested cells would release a surplus of the neurotransmitter resulting in a schizophrenic phenotype. In an effort to prove this point, prior research has tested this theory by administering anti-psychotic drugs directly to the parasite. True to the logic, the treatment eliminated the parasite. It seems that dopamine is essential to the parasite’s survival. Knowing this, most would be quick to suggest that we prescribe anti-psychotics to T. gondii infected individuals and thereby rid them of their invaders. However, although these medications are well tested, I would be wary about such widespread distribution. As mentioned earlier, the opposite of schizophrenia is parkinson’s disease and improper use of anti-psychotics may lead to parkinsonian symptoms.

Beyond the direct relationship between toxoplasmosis and schizophrenia, other behavioral changes have also been observed. In a study conducted by Webster et al. (2007), it was discovered that mice infected with the parasite displayed significantly reduced fear response behavior. In this study, a number of mice were purposefully infected with T. gondii and placed in the presence of cat urine. Un-infected mice in the presence of cat urine quickly recognize the smell and avoid it in any way possible. In contrast, T. gondii mice showed no such fear response and were instead almost attracted to the cat urine. The mechanisms by which T. gondii modulate this behavior is unknown but the consequences are obvious. By reducing the fear response in a mouse, the parasite has an increased chance of being ingested by its desired host, the cat. Sounds oddly intelligent doesn’t it?

So what about humans? Last year I, along with three BYU professors, conducted an epidemiological study investigating the relationship between infection with T. gondii and mood disorders. Specifically, we examined the co-occurrences of T. gondii infection with either Major Depressive Disorder (MDD), General Anxiety Disorder (GAD), or Panic Disorder (PD). Using survey data from the National Health And Nutrition Examination Survey (NHANES) collected by the Center for Disease Control and Prevention (CDC) we statistically predicted the association between T. gondii and the presence of mood disorders. Our results showed no significant statistical association between infection and any of these disorders. Go ahead and breathe the natural sigh of relief that should follow that news. Unfortunaly, mood disorders are only a very small fraction of possible consequences of T. gondii infection. A study by Pedersen et al. (2012) found that infected women were more likely to display disinhibition and inflict self-harm. These observations are consistent with further studies that have found multiple subtle personality differences between infected and non-infected humans. In general, those infected with T. gondii appear to be less anxious, have reduced fear responses, are less diplomatic and are less conscientious (Flegr, 2010; Flegr 2013). Does this sound familiar? These differences, though less severe in magnitude, correspond quite closely with those observed in mice models.

COGNITION

Despite the non-significant results of the first study, my research cohorts and I decided to take one more exploratory step and compare the effects of T. gondii infection on cognitive performance in humans. Cognitive performance is typically defined as a measure of the ability to problem-solve, integrate and hold on to information and to make associations. The same NHANES databases we used previously also contained cognitive functioning data recorded for individuals aged 20-59. Therefore, we compared the incidences of T. gondii infection with each individuals cognitive performance scores. Prepare yourself for a shocker. Our results showed a significant association between infection and cognitive performance. Specifically, we observed a negative association. This means that the more infected an individual was (measured by the quantity of T. gondii specific antibodies in the blood), the lower they scored in cognitive performance testing.

Though it is interesting that T. gondii infection appears to affect cognition in humans, we should not conclude that the parasite purposefully seeks out and interferes with the cognitive centers of our brains. It has been shown through histological and MRI studies of the brain that T. gondii will infect any part of the brain it encounters and that it is not partial toward one certain area over another. Despite its generality, the parasite may still have greater impacts on some areas of the brains than others. Considering diseases such as dementias and Alzheimer’s, it is not a mystery that areas of higher-order thinking (primarily memory centers) in the human brain are more susceptible to insult from foreign bodies. This may be due to the fact that these areas are more plastic or, in other words, are more willing to rearrange and adjust neural networks. In fact, prior research performed by Katan et al. (2013) has shown that a mere infectious burden is enough to affect cognitive performance. This study found that an individual who is fighting a greater number of infectious agents (parasites, bacteria, viruses, etc.) will display reduced cognitive functioning.

IMMUNITY

At this point it seems that T. gondii is nothing but an enemy to a third of the world population. Though it is true that the consequences of infection appear to significantly lean towards the negative, the scale does not fully tip. A recent study by Jung et al. (2012) found that the presence of T. gondii may in-fact be a positive situation for individuals who are facing degenerative disorders such as Alzheimer’s disease and similar dementias. Alzheimer’s disease is caused by the build-up of amyloid plaques which, once aggregated, disrupt neuronal connections and induce a strong inflammatory response. This inflammatory response in turn results in further and more widespread neuronal death. Recall from the introduction of this post that T. gondii is capable of persisting in the human brain by forming an intracellular cyst. This cyst is responsible for holding off the typical inflammatory response that should have destroyed the parasite. In their research, Jung et al. (2012) found that T. gondii and its encapsulating cyst is capable of not only preventing its own inflammatory destruction, it actually dampens the entire inflammatory response in the area. In short, T. gondii activates its own anti-inflammatory response that counteracts the host’s natural inflammatory response. Tying T. gondii and Alzheimer’s together via their inflammatory experiences, Jung et al. (2012) explored whether the anti-inflammatory activity of T. gondii could reduce the destructive inflammatory effects of Alzheimer’s disease. Since the use of human subjects would be unethical in this situation, the experimental procedures in this study were performed in mice. Two mice groups were organized in order to test their theory: Alzheimer’s w/ T. gondii and Alzheimer’s w/o T. gondii. Comparing the two groups, they found that mice infected with T. gondii had much less plaque build-up and reduced amounts of immunological response factors. In essence, the wrecking ball of Alzheimer’s plaque aggregation was halted before it could do its damage. So, is T. gondii infection protective against Alzheimer’s disease? Perhaps. Is it a potential cure? Not likely. Though T. gondii does seem to have positive effects on neuronal degradation (in certain cases), the potential side effects are numerous and may not justify the use of T. gondii as an actual treatment mechanism. Additionally, intentional infection with T. gondii would likely deposit the parasite in additional areas beyond those actually affected by Alzheimer’s disease. There’s no way to specify where the cysts will form.

CONCLUSION

In the near future I plan to conduct research investigating the effects of T. gondii infection in human adults who have been previously diagnosed with Alzheimer’s disease. Based on the earlier mice studies, the hypothesis could be that T. gondii reduces the effects of Alzheimer’s disease in humans as well. However, I’m not sure that such a clean carry-over can be made. The human brain is far more complex and the differences between infected and non-infected individuals may be much less clear. Nonetheless, the study is absolutely worth conducting if only to answer the un-answered questions.

I do not believe that knowledge of this parasite should cause world-wide movements, however, there are many elements of this parasite that are worth exploring further. Beyond my own questions, I would suggest continuous research exploring how T. gondii is capable of crossing the blood brain barrier and infecting neurons without interception. Additionally, T. gondii should be investigated for its dopamine creating abilities. The ability to synthesize new and natural dopamine is incredible and could potentially be useful in medicine. With the proper ingredients, could a dish of T. gondii become a dopamine ‘farm’? Finally, the power to naturally and safely reduce inflammation in the brain would be invaluable to the fields of neuroscience and neuropsychology. In the end it seems that, at least for awhile, we will have a love-hate relationship with Toxoplasma gondii – the parasite in our brains.

Update (9/21/2014):

In this article I mention two studies conducted by myself and professors from the psychology department at Brigham Young University in Provo, UT, USA. Since the publishing of this article, both have been published in scientific journals. The first (toxo vs. mood disorders) was published in Folia Parasitologica and the second (toxo vs. cognition) in Parasitology. The second is till in press so it’s not yet available. The references are included now in the references list below under Gale.

REFERENCES

Flegr, J. 2010. Influence of latent toxoplasmosis on the phenotype of intermediate hosts. Folia Parasitol (Praha), 57, 81-87.

Flegr, J. 2013. Influence of latent Toxoplasma infection on human personality, physiology and morphology: pros and cons of the Toxoplasma-human model in studying the manipulation hypothesis. J Exp Biol, 216, 127-133.

Gale, S. D., Brown, B., Berrett, A., Erickson, L. D., & Hedges, D. W. Association between latent toxoplasmosis and major depression, generalized anxiety disorder and panic disorder in human adults. Folia Parasitol. 61(4): 285-292.

Gale, S. D., Brown, B., Erickson, L. D., Berrett, A., & Hedges, D. W. (In press). Association between Latent Toxoplasmosis and Cognition in Adults: A Cross-Sectional Study. Parasitology. xx: xxx-xxx

Henriquez, S. A., Brett, R., Alexander, J., Pratt, J. & Roberts, C. W. 2009. Neuropsychiatric disease and Toxoplasma gondii infection. Neuroimmunomodulation, 16, 122-33.

Jung, B., Pyo, K., Shin, K., et al. 2012. Toxoplasma gondii Infection in the Brain Inhibits Neuronal Degeneration and Learning and Memory Impairments in a Murine Model of Alzheimer’s Disease. PLoS One, 7(3), e33312.

Katan, M., Moon, Y. P., Paik, M. C., Sacco, R. L., Wright, C. B. & Elkind, M. S. V. 2013 Infectious burden and cognitive function. Neurology, 80, 1209-1215.

Montoya, J. G. & Liesenfeld, O. 2004. Toxoplasmosis. Lancet, 363, 1965-76.

Pedersen, M. G., Mortensen, P. B., Norgaard-Pedersen, B. & Postolache, T. T. 2012. Toxoplasma gondii infection and self-directed violence in mothers. Arch Gen Psychiatry, 69, 1123-1130.

Webster, J. P. 2007. The effect of Toxoplasma gondii on animal behavior: playing cat and mouse. Schizophr Bull, 33, 752-756.