Toxoplasma gondii

• 1. Introduction

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  Toxoplasma gondii is a single-celled parasite, and serological studies suggest that up to half of all people on Earth have been exposed to it. Most of them never know. Infection rates vary widely from country to country, and the highest antibody rate reported as of 2018 was 64.2 percent, in Ethiopia.

  The parasite can infect almost any warm-blooded animal, from pigs and sheep to birds and humans. Yet one particular family of animals holds the key to its sex life, and no other host will do.

  That restriction raises odd questions. Why would a microbe be so picky about where it reproduces? Why do infected rodents seem to lose their fear of danger? Can a parasite that sits quietly in the human brain and muscle change how people think and act? And what happens when it washes into the sea?

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• 2. Cats Only

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  A cat that eats an infected mouse swallows the parasite's tissue cysts, and that is the start of the only sexual stage in the parasite's life. The parasite survives the stomach and invades the lining cells of the cat's small intestine. Inside those cells it reproduces sexually and produces millions of thick-walled cysts called oocysts.

  Biologists call the cat family, wild or domestic, the definitive host. Every other animal, humans included, is an intermediate host, where the parasite can only multiply asexually.

  The reason lies in a missing enzyme. Cats do not express delta-6-desaturase in their intestines. This enzyme normally converts linoleic acid, so without it the fatty acid builds up throughout the cat's body. Recent findings show that this excess is essential for the parasite's sexual reproduction.

  When the infected intestinal cells rupture, the oocysts are released and leave the cat in its feces. From there they reach soil, water, food and anything else the feces touch. They are tough, and in cold, dry climates they can stay infectious for many months.

  Cats can catch the parasite from oocysts too, but they are far less sensitive to them than other hosts are. Their usual route of infection is the one that began this story, which is eating tissue cysts in prey.

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• 3. Shape-Shifting Stages

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  Tissue cysts range from five to 50 micrometers across, and the largest are about two-thirds the width of a human hair. Each cyst is one stage in a life that includes several distinct forms of the same cell.

  When an animal swallows an oocyst, sporozoites emerge and enter cells in and around the intestinal lining. There they become tachyzoites, the fast-dividing, mobile form that spreads through the bloodstream to every organ, including the brain. Inside host cells, tachyzoites multiply in a bubble made from the host's own membrane until the cell bursts.

  Tachyzoites carry a puncturing tool at the tip of the cell, called the apical complex. Through it they inject proteins stored in organelles named rhoptries, which help them manipulate the host's immune response. Strains engineered to lose this ability were harmless in live animals.

  The host's immune system eventually forces a change. Tachyzoites convert into slow-dividing bradyzoites, which cluster into tissue cysts, mostly in the brain, the eyes and striated muscle such as the heart. In pigs most cysts sit in muscle, while in mice most sit in the brain. Cysts appear about 7-10 days after infection.

  Those cysts can last as long as the animal does. The likely explanation is that cysts periodically rupture and form again, with a very small share bursting at any moment. As of 2010, nobody knew what triggers a rupture.

  Inside a cat, bradyzoites become a fourth form, the merozoite, which multiplies quickly before switching to sexual stages. Scientists struggle to study this step because the sexual stages cannot be cultured in the laboratory. One recent finding showed that depleting two parasite transcription factors, AP2XI-2 and AP2XII-1, induces merozoite-specific gene activity, which may eventually allow the full sexual cycle to be grown in a dish.

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• 4. Puppet Rodents

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  In an experiment led by Berdoy and colleagues, infected rats chose the area scented with cat odor over the area scented with rabbit. Healthy rats avoid cat smell, so the infected animals had lost an instinct that normally keeps them alive.

  Studies in mice found something broader. Infection lowers general anxiety, increases exploring, and erases the fear of predators in general. Researchers call this the manipulation hypothesis. A rodent that wanders near cats is more likely to be eaten, and the cat is the one place the parasite can reproduce sexually.

  The idea fits what biologists call an extended phenotype, where a host's behavior bends to serve the survival of another organism's genes. The changes appear to work through epigenetic remodeling in the neurons that govern those behaviors.

  Dopamine is one suspected lever. The parasite carries two genes for an enzyme that handles two rate-limiting steps in making dopamine. One gene is always switched on, and the other is active only while cysts are developing. Infection also leaves long-lasting epigenetic marks that raise the activity of vasopressin, a probable reason some changes persist after the infection is gone.

  Sex matters too. Infected male animals show higher testosterone than uninfected males, while infected females show significantly lower levels than uninfected females. Infected mice also move less well than uninfected mice.

  A 2022 study in Communications Biology followed a well-documented population of wolves through their lives. Infected wolves seemed bolder, took more risks and were more likely to take leadership roles or found new packs. In some cases an infected wolf became the only breeding male in its pack.

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• 5. Human Questions

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  After exposure, a healthy adult may have mild flu-like symptoms for the first few weeks and then feel nothing at all. This quiet state is called latent infection. For infants and people with weakened immunity, however, the same parasite can cause serious toxoplasmosis.

  Researchers have linked the latent state to subtle shifts in behavior, mood and personality. Studies using Cattell's 16 Personality Factor questionnaire found that infected men scored lower on rule consciousness and higher on vigilance. The pattern ran the other way for infected women, who came across as warmer, more outgoing and more conscientious. Infected men were described as more suspicious and jealous and more likely to disregard rules.

  The list of reported associations is long and sometimes startling. A meta-analysis of 23 studies found antibodies to the parasite significantly more common in people with schizophrenia, with an odds ratio of 2.73. A study of 7440 people in the United States found infection 2.4 times more common in people with a history of bipolar disorder type 1 symptoms. Infected subjects were reported to have a 2.65 times higher risk of traffic accidents, and a Turkish study found the same among drivers.

  One line of work looked at business. Students who tested positive were 1.4 times more likely to major in business and 1.7 times more likely to emphasize management and entrepreneurship. Among 197 people at entrepreneurship events, exposure was linked to being 1.8 times more likely to have started a company.

  Many of these findings are contested. A 2016 study found no significant link with schizophrenia, though its authors warned that small samples might have hidden a real one. In one reaction-time test, infection explained less than 10 percent of the variation in performance.

  One biochemical clue involves the immune system's own defense. Interferon gamma activates enzymes that destroy tryptophan, starving the parasite but also lowering tryptophan in the brain, a change tied to depression. Even so, there is no evidence that antiparasitic drugs, azithromycin included, help people diagnosed with schizophrenia.

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• 6. Routes of Infection

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  Just one cyst eaten by a cat can lead to thousands of oocysts, and those oocysts can survive more than a year in contaminated soil. That durability is why the parasite reaches people in so many ways.

  Eating raw or undercooked meat is a leading route, and in the United States the most common threat is undercooked pork. Lamb is also a risk. Other routes include unwashed vegetables, contaminated water, handling cat litter, and unpasteurized goat milk. Sewage and shellfish can carry it as well, and the source notes California seawater as a likely case. It can pass through a blood transfusion or an organ transplant, or cross the placenta from mother to fetus.

  Whether living with a cat is itself a major risk is disputed. Some studies tie infection to households with a cat that uses a litter box, especially with kittens, while others find no significant risk. The parasite has also been shown to spread sexually in brown rats, sheep and dogs.

  Prevention advice in the source draws on the United States Centers for Disease Control and Prevention and the Mayo Clinic. Freezing meat for several days at 0 °F, which is -18 °C, rarely leaves cysts alive. Whole cuts of red meat should reach at least 145 °F, ground meat 160 °F, and poultry 165 °F.

  Oocysts need at least a day after shedding before they become infectious, so scooping litter daily cuts the risk sharply. Gloves help when gardening, sandboxes should be covered, and cat feces should never be flushed. Pregnant women and immunocompromised people should avoid handling litter altogether.

  Treatment is limited. Active toxoplasmosis in humans is treated with pyrimethamine and sulfadiazine plus folinic acid, but no treatment exists for chronic infection, because drugs cannot clear dormant cysts in the brain and muscle. For that reason the infection can reactivate in people with HIV/AIDS or on immunosuppressive therapy. No human vaccine is approved. Sheep, though, can receive a live vaccine called Toxovax, which gives lifetime protection.

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• 7. Wildlife in Trouble

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  Only 54 Māui dolphins over the age of one remain, and T. gondii is counted as a significant human-caused threat to them. The parasite has also been confirmed as a killer of Hector's dolphins in New Zealand, spinner dolphins off Hawaii, and bottlenose, Risso's and striped dolphins along the Mediterranean coast. Fatal cases are also known in Indo-Pacific humpback dolphins in Australia and bottlenose dolphins in Brazil.

  In Canada, antibody rates in the endangered St. Lawrence Estuary belugas rose from 27 percent in 2000 to 44 percent in 2018, and at least five deaths were blamed on toxoplasmosis.

  Sea otters show the pattern clearly. A museum exhibit in San Diego states that urban runoff carries cat feces into the ocean, where it can kill them. In an examination of 105 beached otters, 38.1 percent had parasitic infections, and 28 percent of those infections caused fatal brain inflammation. T. gondii was the root cause in 16.2 percent of those deaths, and a close relative, Sarcocystis neurona, in 6.7 percent. Otters keep sea urchins in check, which protects kelp forests, so their losses ripple outward.

  Minks, which are semiaquatic, eat a similar diet and also test positive. They move across land more freely than otters, so they may carry the parasite to other mammals. The parasite has killed at least 12 endangered Hawaiian monk seals, and one fatal case is documented in a West Indian manatee.

  Penguins are under-studied, yet 57 of 132 Magellanic penguin samples, or 43.2 percent, were positive. Magdalena Island, where they live, has no cats but many human visitors, which hints at other routes.

  Scientists have found oocysts can survive in seawater for at least six months. One hypothesis for transmission involves Acanthamoeba, a water amoeba that can shelter oocysts for at least 14 days.

  Birds suffer too. Canaries and pigeons fare badly, often dying quickly, and blindness is common in canaries. Michael Grigg of the National Institute of Allergy and Infectious Diseases found the parasite in more than half of dead raptors and more than one third of dead seabirds he examined.

  Standard physical and chemical treatments at water plants have proven ineffective against oocysts, while research shows that UV-C light can inactivate them.

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• 8. Naming the Parasite

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  In 1908, at the Pasteur Institute in Tunis, Charles Nicolle and Louis Manceaux found an unfamiliar organism in the tissues of a gundi, a hamster-like rodent. They first called it "Leishmania gondii" before realizing it was a new genus. Toxoplasma comes from Greek words for "bow" and "shape," a nod to its curved form, and gondii honors the gundi.

  The same year, Alfonso Splendore saw the organism in a rabbit in Brazil but gave it no name. In 1914 the Italian Aldo Castellani was the first to suspect it could affect humans.

  The first conclusive human case was an infant girl born by Caesarean section on the 23rd of May 1938 at Babies' Hospital in New York City. She had seizures at three days old, and doctors found lesions in the maculae of both eyes. She died at one month. Her autopsy revealed the parasite in brain and eye tissue, and rabbits and mice injected with her tissue developed encephalitis.

  The meat question came next. In 1954, D. Weinman and A.H. Chandler proposed that undercooked meat could transmit it, and in 1960 researchers showed that stomach enzymes dissolve the cyst wall. In 1965, Georges Desmonts and colleagues tested the idea on children in a Paris sanatorium. After a year of two rare portions of beef or horse meat daily, infection rose from 10 percent to 50 percent, and to 100 percent in children fed rare lamb chops.

  A 1959 study in Mumbai had complicated the picture by finding similar infection rates in strict vegetarians. Then, in 1970, oocysts turned up in cat feces. Later testing found that at least 17 species of felids shed oocysts and no other animals do. In 1984, Elmer Pfefferkorn showed that human interferon gamma could block the parasite's growth in human fibroblasts.

  Modern genetics adds detail. The genomes of more than 60 strains have been sequenced, with 11-14 chromosomes each and 7,800-10,000 proteins in the major strains. A database called ToxoDB collects the results. In 2006, researchers reported that North American and European populations are dominated by three clonal lineages, Types I, II and III, which may share an ancestor about 10,000 years old.

  In July 2024, a study in Nature Microbiology engineered the parasite to deliver the MECP2 protein, a therapeutic target for Rett syndrome, into the brains of infected mice.

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