This post was inspired by the book Gut: The Inside Story of Our Body’s Most Under-Rated Organ by Giulia Enders.

Toxoplasma parasite

Toxoplasma gondii is a a widespread neurotropic protozoan parasite which reproduces in cats’ intestine. It infects about one third of the population worldwide. The probability of a human being infeced is in percents equal to the number of one’s age.

Felids have been identified as the definitive host to T. gondii. Within the cat’s gut the parasite can sexually reproduce and spread via oocysts.

Infection

Humans can get infected by T. gondii via ingestion of the parasite’s oocysts (highly resistant stage of a parasite), which spread from the feces of infected cats. Other routes of transmission include consumption of undercooked meat infected with T. gondii cysts or ingestion of contaminated water. When ingested by an intermediate host, the parasite spreads from the intestine to other organs, finally localizing in muscle and brain. Life-long presence of dormant stages of this parasite in the brain and muscular tissues is considered asymptomatic from the clinical point of view. If there are symptoms during the acute infection, they consist of systemic inflammation, high levels of inflammatory cytokines, and flu-like symptoms.

From the first look of it it may seem like it’s rather unimportant whether we are infected or not. Yet this fact is very important. Toxoplasms affect the brain. Reserchers first performed studies on infected rats and when the experiment was confirmed several times with no deviation, they turned to humans. It has been statistically proven that infected persons get themselves in more risky situations much more often than non infected persons (i.e. intentionally or unintentionally get involved in different kinds of accidents).

In the brain, the parasite hides within neurons and glial cells, intracellularly, in cystic structures. These structures have minimal exposure to cellular and molecular mediators of the immune system. The immune system can thus contain the infection successfully, but cannot remove it.

Research performed mostly on military personnel, university students, pregnant women and blood donors has shown that this seemingly asymptomatic disease has a large influence on various aspects of human life.

How Toxoplasma affects the body and the brain

This parasite’s ability is to alter immune responses, manipulate the immune system and alter behavior of the host.

When infected, the human immune system releases the enzyme indolamine 2,3-dioxygenase. This enzyme is namely quick in breaking down the food for the parasite as a way of organisms’s immune response to remove the parasite – remove its food. This substance, however, is also one of the components necessary for the production of serotonine. When there’s a lack of this hormone in the brain, a person chemically cannot be happy. It’s the body’s compromise – in order to deactivate the parasite it will deal with a lack of serotonine. But no matter what the body’s defence is, once the parasite is in the body it can never be removed. Unhappy people act very differently than happy people. Toxoplasma gondii affects humans through the brain centers for fear, smell and behaviour.

In settles in exactly three parts of the brain: amygdala, smell center and frontal area:

– in amygdala it affects the sense of fear, the act of being afraid, it decreases it, thus making people more wreckles. And with the combination of serotonine lack, it’s life-threatening.

– when it affects the sense of smell, it affects the infectees’ reactions to certain scents. The modern human is not a natural host of Toxoplasma, rats are. The most researched and obvious reaction is to cat urin. It stinks horribly, but not to the infected, rats even become attracted to it, when their normal reaction would be to flee as there is a predator, a cat, around.

– in the frontal area it affects more complicated decisions; whether to drive faster, to hurt ourselves or others. It goes as far as for some to become suicidal.

In the brain T. gondii transforms from tachyzoite (rapidly growing life stage) to bradyzoite (slowly replicating life stage found in the tissue cyst) forms under the pressure of the adaptive immune response. The bradyzoite live in cystic structures that persist for the life of the individual, occasionally release bradyzoite that are able to infect other cells and transform into tachyzoites for a brief time, trigering the immediate response from the adaptive immune system. Immunodeficiency may also result in toxoplasmic encephalitis. The immune response in the brain also involves activation of immune mechanisms implicated in suicide risk factors.

Immune Responses to T. gondii

Note: if you’re not interested in the biology of the infection, skip this paragraph and simply move to the next one.

Multiple cells types are involved in resistance:

• production of IFN-γ by T cells and NK cells is critical to resistance to T. gondii.
• IL-12 production is also critical, as the absence of IL-12 disables replication, probably via a reduced production of IFN-γ. Both IL-12-deficient as well as IFN-γ-deficient animals succumb to infection. The major source of IL-12 in vitro appeared to be the macrophages, but more recent work in vivo reveals it’s dendritic cells (which synthesize it) and neutrophils (which have it prestored in vacuoles to be released upon contact).

In addition to the innate immunity mechanisms described above, adaptive immunity mechanisms including nongermline-encoded clonal receptors BCR and TCR are essential for long-term resistance. A major expansion of B cells results in high levels of IgM (acute infection) and IgG (chronic infection). These antibodies opsonize extracellular parasites and induce complement activation and lysis, as well as phagocytosis by macrophages.

Initiation of the adaptive immune response is dependent upon presentation by accessory cells, of peptides derived from the parasite in the context of MHC molecules. The parasite-derived MHC class I molecules could be presented to CD8⁺ T cells by any cells but most commonly by infected cells, while MHC class II molecules can be presented to CD4⁺ cells by dendritic cells (predominantly), macrophages and B cells.

After priming, T cells acquire cytolytic properties against infected cells. However, in toxoplasmosis the main role of T cells is to produce IFN-γ, which controls parasite replication.

Immune and behavioral manipulation

T. gondii uses the immune system for its spread through the body. The manipulation of the immune system starts in the small intestine, where T. gondii starts replicating in the lamina propria. Immature dendritic cells are recruited by the chemokine-like activities of the parasite in the small intestine, further amplified by inflammatory cells attracted at the site of infection. Dendritic cells and monocytes that cross the lamina propria in the intestine act as Trojan horses to safely send T. gondii to its final tissue destination, including the brain. In order to survive, T. gondii must ensure not only its own survival, but also the survival of its host (it is unlikely that cats will eat corpses). Thus, T. gondii plays a sophisticated balancing game between signaling, allowing itself to be detected by the immune system and also avoiding complete elimination by the immune system.

Normally rodents instinctively avoid feline odors. But infection with T. gondii caues a reduction in avoidance of and even attraction to feline odors. The attraction appears specific for felids and is not present for odors of other predators. The infected rodents become more vulnerable to predation and also contribute, unwillingly, to T. gondii reproduction. This phenomenon is an example of behavioral manipulation of the host by parasite. In addition, nonspecific effects of decreasing neophobia have also been discovered. A decrease in neophobia is likely a consequence of the functional impairment of fear circuits in the amygdala, where T. gondii predominantly localize.

Possible dangers

Research in rodents has revealed that T. gondii localizes in multiple structures of the brain, including the prefrontal cortex and the amygdala. These areas have a primary role in emotional and behavioral regulation and they show major histopathological changes in suicide victims. It is possible that because T. gondii occupies these areas, the infection may disrupt the affective and behavioral modulation and thus elevating the risk of suicide. The immune activation in the defense against the parasite leads to elevation of cytokines related to behavioral changes, suicidal behavior, occurrence of induced self-destructive behavior and mental illness.

The influence of a recent (subacute) Toxoplasma infection on the rate of traffic accidents is relatively strong. Toxoplasmosis increases the reaction time of infected subjects, which can explain the increased probability of traffic accidents in infected subjects. Drivers diagnosed with acute and subacute toxoplasmosis should be informed about the transiently increased risk of traffic accidents.

Toxoplasma also appears to be involved in the initiation of more severe forms of schizophrenia. Toxoplasma-infected schizophrenic patients differ from Toxoplasma-free schizophrenic patients by brain anatomy and by a higher intensity of the symptoms of the disease.

T. gondii mediates in an increased vulnerability to suicide attempts in those hosting it. The mechanisms may include heightening of risk factors for suicide such as depression, impulsivity, aggression and reduction of fear (especially fear of death).  Studies showed that patients with repetitive depression had higher values for antibodies to T. gondii higher than the normal control group.

Sources:

– Flegr, J. Influence of latent Toxoplasma infection on human personality, physiology and morpgology: pros and cons. 2013

– Okusaga, O. Toxoplasma gondii, the immune system and suicidal behavior. 2012

– Flegr, J. Increased incidence of traffic accidents. 2009

– https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/tachyzoite

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