For healthy people, Toxoplasma gondii infection may not show significant symptoms. In other words, you may have been infected without knowing it. However, nerve damage caused by latent Toxoplasma gondii may have left a profound impact on human nerves and psychology.
Written by | Tao Yu (Indiana University School of Medicine, USA)
Scary zombie ants
In the documentary Planet Earth, David Attenborough describes a zombie ant manipulated by a terrifying parasitic fungus. A spore called Cordyceps controlled the minds of bullet ants in a powerful and cruel way after invading their bodies. After invading the brain of the bullet ant, this parasitic spore will cause the bullet ant to lose its sense of direction and bite the stalk of the plant with its jaw like a zombie. It took about three weeks for the fruiting bodies of cordyceps bacteria to grow out of the bullet ant's head, a long and terrifying process.
Video: How Cordyceps bacteria kill bullet ants (Go to the "Back to Park" public account to watch)
To figure out the significance of fungal infections changing ant behavior, scientists conducted an in-depth study of camponotus leonardi in Thailand's rainforests. Scientists have found that normal carpenter ants travel in specific directions and rarely get lost, and after being infected with the eccentric cordyceps fungus (Ophiocordyceps unilateralis s.l.), the wood ants become random like headless flies and twitch, with the result that they fall off the treetops and can no longer return to the dry and hot canopy, living only within about 25 centimeters above the ground. It's cold and humid, making it a great environment for fungal life. Something even more terrifying happens when the noonday sun is at its strongest— when the fungus that invades the wood ant's brain begins to manipulate the wood ant, forcing the wood ant to bite the vein of a leaf like a zombie. Fungi are far more powerful than that, multiplying in large numbers in the brains of wood ants, causing the jaw muscles of wood ants to atrophy extensively, causing their jaws to invade deep tissues and form a "lock-jaw." As a result, after the wood ants die, their bodies are still firmly tied to the leaf veins, a phenomenon known as the "Death grip." After a few days, the fungus grows a fruiting body from the head of the wood ant and scatters new spores, infecting other wood ants.
In fact, the parasites that can manipulate host behavior are far more than cordyceps, and some microorganisms or parasites can even affect the human brain and behavior, such as the famous Toxoplasma gondii.
Toxoplasma gondii – one of the most "successful" parasites
Toxoplasma gondii is hailed by scientists as one of the most "successful" parasites because it can infect almost all warm-blooded animals. It is estimated that about 30 to 35 per cent of the world's population has been infected with Toxoplasma gondii. Many people may know about Toxoplasma gondii from the saying: "Pregnant people can't keep cats." Although this sentence does not seem to be completely accurate now, its influence is enough to make many popular science workers unattainable. In fact, scientists have discovered Toxoplasma gondii more than 100 years ago.
In 1908, Charles Nicolle, a scientist at the Institut Pasteur in Tunis, studied in North Africa the host of Leishmania, a dangerous pathogen capable of causing human kala-azar. Charles believes that a rodent comb rat (Ctenodactylus gundi) living in the foothills and mountains of southern Tunisia may be the natural host of Leishmania. In the course of his research, Charles inadvertently discovered another parasite in a completely different form from Leishmania. He named it "Toxoplasma Gondii" (Toxoplasma Gondii) based on its host and bow-like shape. After careful exploration by many scientists, the life cycle of Toxoplasma gondii and many pathogenic mechanisms have now been clarified.
Different forms of Toxoplasma gondii. a. Tachyphon, b. Schematic diagram of the internal structure of the tachyzoite, c. Capsule, which is filled with a large number of bradyzoites, similar in morphology to tachyzoites, but with a smaller insect body. 丨Source: https://www.jotscroll.com/forums/11/posts/204/toxoplasma-gondii-life-cycle-parasite-transmission-diagnosis-test.html
Cats are one of the most intimate pets of humans and are also the hosts of Toxoplasma gondii. Toxoplasma gondii can complete the entire life cycle in the small intestine of a cat. Unfortunately, cats are also the ultimate host of Toxoplasma gondii, which means that Toxoplasma gondii can complete sexual reproductive processes in the cat's intestines while producing a large number of egg sacs. Cats infected with Toxoplasma gondii release a large number of egg sacs when defecating. After the egg sac is excreted by the cat, it will continue to develop mature spores in environments such as cat litter, and humans or other animals will be infected after contact with the egg sac containing mature spores. But one thing to worry about is that humans are not the ultimate hosts of Toxoplasma gondii, and humans infected with Toxoplasma gondii do not spread eggs everywhere.
Although veterinarians already have ways to diagnose and treat toxoplasmosis in cats, and scientifically fed cats are not easily infected, mothers who are pregnant with babies still have to be doubly careful. This is because the mother, after being infected with Toxoplasma gondii, can easily spread to the fetus in the stomach and cause serious consequences. If the infection occurs shortly before pregnancy or in the first trimester of pregnancy, mother-to-child transmission occurs in approximately 10% of cases, followed by miscarriage or severe fetal malformations such as hydrocephalus and microcephaly. If the infection occurs in the third trimester, the probability of the fetus becoming infected rises to 50% to 60%. So during pregnancy and pregnancy, the work of shoveling is temporarily left to Bao Dad.
But there's a question, is it okay if someone who isn't pregnant is infected with Toxoplasma gondii?
Acute toxoplasmosis is usually a self-limiting disease with possible symptoms including fever, fatigue, headache, and cervical lymphadenopathy. In immunocompromised individuals, Toxoplasma gondii infection can lead to severe symptoms and even death. Fortunately, healthy people with a normal immune system usually do not develop severe symptoms even if they are infected with Toxoplasma gondii, and many people do not even know when they were infected. However, with the deepening of scientific research, people have gradually realized that patients who do not have acute symptoms of hidden or chronic infections may actually develop another form of symptoms. And that starts with a cat and mouse story.
Take the initiative to find the cat to single out the mouse
The rat's fear of cats seems innate. If a lab-bred mouse is placed in a box and a few drops of cat urine are dripped in one corner of the box, the mouse will actively avoid the corner where cat urine is present. At the same time, the hormone levels associated with stress in the mice also rose, which made the mice more alert and less sensitive to pain. However, mice infected with Toxoplasma gondii do not avoid corners where cat urine is present, and some infected mice are attracted to the smell. This strange phenomenon has really opened the eyes of scientists.
Through further research, the scientists found that the reduced aversion to feline odors in rodents infected with Toxoplasma do not appear to be due to impaired olfactory function, but rather a change in the host's perception of the risk of predation. There are complex neural and physiological changes behind this, and scientists currently generally believe that neurotransmitter levels or metabolic changes and hormone levels may be the main reason why Toxoplasma gondii affects rodent behavior.
In fact, Toxoplasma gondii infection increased dopamine signaling in the mice's brains. For example, studies have found that infected mice have formed toxoplasmosis cysts in the brains, which contain large amounts of dopamine. Dopaminergic cells (i.e., nerve cells that synthesize and release dopamine) also secrete more dopamine after infection with Toxoplasma gondii. Although infected mice showed stronger exploratory behaviors in behavioral experiments, this behavioral change disappeared when their dopamine pathways were inhibited. These findings all suggest an association between Toxoplasma gondii infection and changes in the dopaminergic neuromodulatory system.
Dopamine, on the other hand, is a neurotransmitter associated with reward or pleasure and also affects the host's motivation and goal-oriented behavior. Scientists believe that parasitic Toxoplasma gondii interferes with mice's behavior by increasing dopamine signaling, prompting it to develop an atypical motivation to explore predator odors. Another study found that toxoplasma gondii, after infecting dendritic cells in the brains of mice, prompted it to secrete more γ-aminobutyric acid,γ which is an important inhibitory neurotransmitter in the brain and has the effect of reducing fear and anxiety.
However, a study published in 2020 challenged the story of mice and cats. The study found that Toxoplasma gondii alters mice's aversion to predators, but this change in disgust is not selective. In other words, toxoplasma gondii infection doesn't prompt rats to go specifically to cats to die— they may find other animals. In fact, both fox (predator) and guinea pig (non-predator) odors may attract infected mice. From this, the study suggests that Toxoplasma gondii reduced the levels of general anxiety in infected mice, increasing their exploratory behavior and curiosity, which led to these behavioral changes.
In addition, the study also found that the severity of the behavior changes in mice was related to the number of cysts caused by Toxoplasma gondii in the brain, and the levels of pro-inflammatory cytokines triggered by cysts seemed to be related to the behavior changes in mice. This suggests that Toxoplasma gondii infection not only promotes the predatory feeding of rodents by end-host cats, but also increases the success rate of other rodent predators, which is also conducive to the spread of Toxoplasma gondii between intermediate hosts.
Toxoplasma toxoplasma has also been found to invade the testicles of rats and lead to increased synthesis of testosterone in testicular stromal cells, which causes rats to turn to sexual behavior rather than defensive behavior. On the other hand, in female rats, toxoplasmosis infection can also affect progesterone levels. What other effects does Toxoplasmosis infection have on rodent behavior? How is it affected? There are still many unknown secrets waiting for scientists to explore.
Could schizophrenia be due to infection with Toxoplasma gondii?
Although we should be very cautious when applying the findings of mouse behavior directly to human behavior and psychology, it is clear that the inflammatory response of the central nervous system caused by Toxoplasma toxoplasma infection leads to neuronal damage associated with neurodegenerative diseases and can trigger Alzheimer's disease. Therefore, the potential effects of Toxoplasma gondii infection on human neuronal function should not be underestimated.
—— Boillat M. et al, Cell Reports, 2020
Although acute toxoplasma gondii infections do not usually cause obvious symptoms, a growing body of research has revealed a link between chronic toxoplasmosis infections and human behavioural changes and mental illness. Studies in recent decades have shown a potential link between latent Toxoplasma toxoplasma infection and an increased risk of Parkinson's disease, Alzheimer's disease, occult epilepsy, recurrent migraine, autism, obsessive-compulsive disorder, and brain tumors, as well as risk factors for psychiatric disorders such as schizophrenia, depression, generalized anxiety disorder, personality disorders, and bipolar disorder.
Toxoplasma gondii and infected cells. | Source: https://blogs.unimelb.edu.au/sciencecommunication/2014/09/09/the-parasites-in-you/
Latent toxoplasmosis infections in the population can lead to impaired brain function, leading to widespread behavioral changes and neuropsychiatric changes. Latent Toxoplasma gondii infections may alter impulse control, triggering more general risk-taking behaviors and violent behaviors. The study found that female individuals who were seropositive for Toxoplasma gondii showed higher aggression, while male individuals were overly impulsive. In terms of neurocognitive function, toxoplasma gondii latent infections have been associated with decreased psychomotor performance, inattention, decreased intelligence quotient (IQ), and altered personality traits in humans. Overall, the above attributes may affect personality phenotypes and can ultimately lead to a variety of life- and health-risking behaviors, including suicide and other homicide.
A study of 97 male autopsy case samples by pathologists from the Department of Forensic Sciences at the Medical University of Warsaw in Poland between 2010 and 2013 found that the presence of toxoplasmosis genome DNA in the brain, while not associated with excessive alcohol consumption, was strongly associated with the occurrence of death. A 2003 study, which tested 857 conscripts using a modern psychobiology questionnaire, found that toxoplasmosis-positive people scored low on the three scales of impulsiveness, extravagance, and Disorderliness compared to healthy people who were not infected with Toxoplasma gondii. To the surprise of the testers, the positive subjects had lower IQs and lower chances of getting higher education than the healthy subjects.
A study published in 2002 surveyed 146 drivers/pedestrians involved in traffic accidents and compared it with the general population living in the same area found that the seroprevalence rate of Toxoplasma gondii in the traffic accident group was significantly higher than that of the general population. The study also calculated that the risk of traffic accidents in people with latent toxoplasmosis infection was 2.65 times higher than that of people with negative Toxoplasma gondii. Although the factors that cause traffic accidents are numerous and complex, chronic toxoplasma toxoplasma infection drivers do take longer to react than healthy drivers. At the same time, non-compliance with traffic rules is also one of the characteristics of patients with toxoplasmosis.
There is a strong correlation between chronic Toxoplasma gondii infection and risky behaviors that can lead to death. The current findings suggest that the widespread spread of toxoplasmosis can lead to hundreds of thousands of deaths worldwide, including road traffic accidents, work accidents and suicides. These findings point to the need for regular toxoplasmosis screening for people in high-responsibility occupations, such as pilots, air traffic controllers or professional drivers. Adequate treatment of infected people may reduce the number of road accidents and suicides, and reduce people's risk of neuropsychiatric diseases.
Through studies in mice and humans, scientists have found that Toxoplasma gondii has a strong appetite for the central nervous system. The effect of Toxoplasma gondii on human behavior may be related to the location of the parasite in specific areas of the brain. Cysts formed by Toxoplasma gondii can be found throughout the brain, but occur preferentially in the cerebral hemisphere, hippocampus, amygdala, basal ganglia, cerebellum, cerebral cortex, brainstem, and olfactory bulb. The amygdala is an area of the central nervous system associated with fear and anxiety, and a 2007 study published in PNAS suggested that toxoplasma cysts within the amygdala may be key to influencing changes in host behavior.
Cysts (white parts) formed by Toxoplasma gondii in the human brain 丨Source: https://microbewiki.kenyon.edu/index.php/File:Oit_c3_d04.png
Toxoplasma gondii can infect not only neurons, but also a variety of cells such as microglia and astrocytes. Toxoplasma gondii's brady protozoa can inhibit apoptosis and live in the cells of the host for many years or until the end of the host's life. Toxoplasma gondii cysts in the brain parenchyma trigger a variety of cells to secrete inflammatory cytokines and chemokines, and a sustained local neuroinflammatory response is also considered to be one of the factors that trigger various neuropsychiatric behavioral changes. Similar to rodents, Toxoplasma gondii can trigger changes in the dopamine pathway and other neurotransmitter pathways in the human brain, which in turn affect the brain's response to motor control, motivation, pleasure, addiction, reward, and fear.
Why do microbes and parasites change the behavior of their hosts?
The Rodent-T. gondii model is one of the most studied models of parasitic behavior manipulation by scientists. After infecting rodents such as mice, Toxoplasma gondii makes it easier to be preyed upon by cats by changing their brains' perceptions of fear and increasing their curiosity. In this way, Toxoplasma gondii can smoothly enter the cat's body and produce a large number of egg sacs in the final host, infecting more hosts.
Whether it's a fungus that turns ants into zombies or toxoplasmosis that emboldens mice, microbes and parasites that change host behavior often have a specific selective advantage over themselves:
A range of respiratory-transmitting pathogens, such as influenza viruses and coronaviruses, cause coughing and sneezing by stimulating the host's respiratory tract after infecting the host, and spread efficiently with the help of aerosols produced by the host. Respiratory pathogens can infect hundreds of millions of people each year through this efficient mode of transmission.
Viruses transmitted by digestive tract routes such as rotavirus and norovirus can cause severe diarrhea and vomiting in the host after infection. Large amounts of viral particles spread into the environment through vomit and feces, and infect other hosts through a new round of the "fecal-oral pathway."
Dogs with rabies exhibit higher levels of aggression and biting behavior. Because sick dogs have a large amount of rabies virus in their saliva, this change in behavior may increase the chances of the virus spreading to susceptible hosts.
Studies of Accidental/dead-end hosts have shown that changing host behavior may also be just a side effect of the selective adaptation of microorganisms and parasites to the host during evolution. For example, sea otters infected with Toxoplasma gondii are more likely to be preyed upon by sharks, but sharks are a "dead end" for Toxoplasma gondii, which is not good for Toxoplasma gondii. Although rabies viruses increase the chance of transmission by changing their behavior after infecting dogs, behavioral changes such as hyperactivity, fear spasms, and severe agitation caused by rabies virus infection in humans do not appear to have a selective benefit to the virus itself. As for the effect of Toxoplasma gondii on human behavior, is it a side effect of selective adaptation or selective adaptation? We don't have an answer to that yet.
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