Toxoplasmosis

• 1. Introduction

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  Toxoplasmosis may be living quietly inside up to half of all the people on Earth, and almost none of them know it. The disease is caused by Toxoplasma gondii, a single-celled parasite that can infect nearly any warm-blooded animal. Yet it reproduces sexually only in members of the cat family. That odd arrangement raises a string of questions. How does a parasite hide for a lifetime inside muscle and brain? Why does it barely trouble most healthy adults but threaten unborn children? And can it nudge the behavior of the animals it lives in, people included? Scientists have linked infection to a variety of neuropsychiatric and behavioral conditions, and the evidence remains hotly debated. The answers begin with the parasite's two very different faces.

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• 2. Hidden Stages

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  Swollen lymph nodes in the neck or under the chin are the most common sign of acute toxoplasmosis, followed by the armpits and the groin. Many healthy adults notice nothing at all. Those who do fall ill often report flu-like misery: headaches, fever, fatigue, and muscle aches that can last a month or more. Adults usually have swelling at a single site, while children more often have several. Recovery times vary. In 60% of cases the nodes shrink within one to two months. A quarter of patients need two to four months, and 8% need four to six. Another 6% wait much longer.

  People with HIV/AIDS, patients on certain kinds of chemotherapy, recent organ transplant recipients, and young children face a harsher version. Headache, confusion, poor coordination, and seizures can set in. Lung problems may mimic tuberculosis or Pneumocystis jirovecii pneumonia, a common opportunistic infection in AIDS. Severe inflammation of the retina, called chorioretinitis, can damage the eyes, and the brain can become inflamed in a condition called encephalitis. Babies infected through the placenta may be born with brain or eye damage, or with nasal malformations, though these outcomes are rare.

  Tachyzoites are the fast-dividing form of Toxoplasma gondii, and they drive the acute phase by spreading through the body's tissues. After multiplying, they convert into slow bradyzoites, sheltered inside tissue cysts that form mainly in muscle and brain. Pressure from the host's immune system helps trigger that switch. Antibiotics do not touch bradyzoites, and the cysts can stay for the host's entire life. If a few bradyzoites wake up in a healthy person, the immune system swiftly destroys them. In fetuses and immunocompromised people, awakened parasites can run rampant and cause serious neurological damage.

  A parasitophorous vacuole is the first tool Toxoplasma gondii builds once it forces its way into a cell. The parasite fashions this protective bubble from the host cell's own membrane. The bubble resists the cell's digestive machinery and can take control of the host's mitochondria and endoplasmic reticulum. Early in the invasion, the parasite releases ROP proteins from an organelle called the rhoptry. These proteins steer the cell's signaling pathways and disable IRG proteins that would otherwise destroy the bubble. Some strains also release GRA15, which switches on the NF-κB pathway and raises the inflammatory signal IL-12, possibly pushing the parasite toward its latent phase. Which proteins a strain can release depends on its genotype, and that shapes its virulence.

  BAX and BAK, two proteins that start cell death, are among the parasite's targets. Toxoplasma gondii bends their shape so they cannot reach the compartments where cell death begins, though it does not lower their levels. It can also trigger autophagy through a calcium-dependent pathway, according to research by Wang and colleagues, leaving fewer healthy cells to attack the infected ones. Another protein, GRA28, travels out through the MYR1 pathway and makes infected cells behave like highly mobile dendritic cells. How hard the parasite hits depends on the strength of the host's immune system and on how many parasites crowd into a single cell.

  Helicobacter felis, Leishmania major, and the parasite Nippostrongylus brasiliensis are among the other threats whose immune response may shift, for better or worse, in a host carrying Toxoplasma gondii.

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• 3. Routes And Reach

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  Pork, lamb, and venison that are raw or only partly cooked can carry tissue cysts, and eating them is a classic way to catch toxoplasmosis. Countries where undercooked meat is traditional show higher infection rates. Cysts can also reach the mouth from hands, knives, utensils, or cutting boards that touched raw meat. Other routes include unwashed fruit and vegetables from soil fouled by cat feces, untreated water, unpasteurized milk, particularly goat's milk, and raw seafood. Gardening, cleaning a litter box, and playing in children's sandpits can all deliver oocysts, which survive in the environment for months.

  Cats are the hinge of the whole cycle. A cat usually picks up the parasite by eating an infected rodent or bird, and shedding begins around the third day afterward. The oocysts are harmless when they leave the cat. About a day later they undergo sporulation and become potentially dangerous. Most infected cats shed only once in their lives, typically for 3-10 days, but the output can reach millions of oocysts. At any given moment, roughly 1% of cats are shedding. Because cats are usually infected in their first six months, buried oocysts can stay infectious from several months to more than a year. Numerous studies find that simply living with a cat is not a significant risk factor, though living with several kittens matters somewhat.

  Heart and lung transplants carry the highest risk of toxoplasmosis, because the striated muscle of the heart can hold cysts. Recipients who lack antibodies and receive organs from recently infected donors are at risk. Recipients with latent infection may see it reactivate under immunosuppression, and stem cell recipients face longer periods of weakened defenses. Screening donors and recipients, and giving treatment, reduces the danger. Studies have also reported the parasite in human semen and proposed sexual transmission, but it has not been established as a main route.

  A survey of 99 studies across 44 countries measured infection among women of childbearing age. Latin America showed the highest prevalence, at roughly 50-80%. Parts of Eastern and Central Europe and of Southeast Asia ran about 20-60%, the Middle East 30-50%, and parts of Africa 20-55%. In the United States, a national health survey called NHANES found that 9.0% of US-born people aged 12-49 carried IgG antibodies in 1999-2004, down from 14.1% in 1988-1994. Among women aged 15-44, 7.7% of the US-born and 28.1% of the foreign-born were positive. Toxoplasma gondii is the second leading cause of foodborne deaths in the country and the fourth leading cause of foodborne hospitalizations.

  Three major types of the parasite, named types I, II, and III, shape the patterns seen around the world. Type II is the one that is virulent in humans across most of Europe and North America. Antibody tests prove exposure but do not guarantee that a person is chronically infected, which is worth remembering whenever a prevalence figure is quoted.

  In the Canadian arctic, Toxoplasma gondii has turned up in a place once considered too cold for it to survive. Higher temperatures lengthen its survival time. More snowmelt and rain can send greater numbers of oocysts down rivers. Shifts in bird, rodent, and insect populations and migrations may change where the parasite spreads, since these animals act as reservoirs and vectors. Urbanization and the degradation of natural environments are also suggested to raise the risk of infection.

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• 4. Pregnancy Risks

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  About 200,000 cases of congenital toxoplasmosis occur each year, and every one begins with the parasite crossing the placenta. When a pregnant woman develops acute toxoplasmosis, tachyzoites have roughly a 30% chance of entering placental tissue and reaching the fetus. The later in pregnancy the infection happens, the likelier the fetus is to be infected. Earlier infection, however, tends to bring poorer outcomes, especially when untreated. A first exposure during pregnancy puts the fetus at particular risk.

  Hydrocephalus, the eye inflammation called chorioretinitis, and intracranial arteriosclerosis form the classic triad of congenital toxoplasmosis. The disease is also tied to fetal death, miscarriage, cerebral calcifications, and encephalopathy, and it can lead to blindness. Sensorineural deafness, seizures, and intellectual disability are further consequences. Most infants infected in the womb show no symptoms at birth but may develop them later. Up to 30% of affected newborns have some degree of sensorineural hearing loss. A 2010 study of 106 patients, all treated before 2.5 months of age, found language disorders in 26.4% of them. A baby's immune system does not fully develop during the first year of life, so these infections can be serious.

  A single blood draw at the first prenatal visit can show whether a woman has met the parasite before. A positive antibody titer signals past exposure and immunity, which largely protects the unborn child. Women with negative titers may be advised to have serology testing as often as monthly, because treatment after a first exposure sharply lowers the chance of passing the parasite on. Diagnostic recommendations also mention testing at three-week intervals during pregnancy.

  Portugal, France, Austria, Uruguay, and Italy screen pregnant women routinely, which most countries do not. Cost-effectiveness and a high number of false positives explain the reluctance. Regional programmes operate in Germany, Switzerland, and Belgium. Invasive prenatal testing carries its own risk, estimated at 18.5 pregnancy losses per case of toxoplasmosis prevented. Because of that, newborn screening is preferred unless fetal abnormalities are spotted.

  Practical advice for pregnant women is straightforward. Avoid handling raw meat, drink no raw milk, especially goat's milk, and skip raw or undercooked meat of any type. Stay away from cat feces, and either avoid gardening or wear gloves for it. Evidence that education before pregnancy prevents congenital toxoplasmosis is thin. Still, teaching parents before the birth may improve food, personal, and pet hygiene.

  In 2006, a Czech research team reported that women with high toxoplasmosis antibody levels were significantly more likely to give birth to boys. Births are normally about 51% boys, but infected people had up to a 72% chance of a boy.

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• 5. Testing And Treatment

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  In about 50-80% of cases, brain scans cannot easily separate toxoplasmosis from primary central nervous system lymphoma. Both cause brain lesions, and the lesions sit where a biopsy would be too risky. The main clue is that lymphoma typically produces a single lesion near the brain's fluid-filled spaces, while toxoplasmosis produces several scattered through the basal ganglia. Other lookalikes include metastatic brain lesions, progressive multifocal leukoencephalopathy, tuberculosis of the nervous system, bacterial or fungal abscesses, cytomegalovirus, and herpes simplex encephalitis.

  IgG antibodies usually appear within a week or two of infection, peak within one to two months, and then persist for life. A positive result therefore cannot say whether infection is recent or old. An IgG avidity test helps. Early IgG grips the parasite weakly, and a strong grip means the infection began three to five months before testing. That timing matters most in congenital cases. IgM antibodies appear about a week after infection and fade within one to six months, though 25% of people are already negative by seven months. IgM can linger for years, and false positives for acute infection are possible. Commercial kits often have low specificity, and their results are frequently misinterpreted.

  A 2021 systematic review evaluated twenty commercial IgG assays against an accepted reference method. Sensitivity ranged from 89.7% to 100% at standard titers but only 13.4% to 99.2% at low titers. Specificity ran from 91.3% to 100%. Serology has a blind spot, because antibodies may not rise until several weeks into infection. A pregnant woman could test negative during active infection, and antibody levels may not rise at all in immunocompromised patients. PCR can detect the parasite's DNA in amniotic fluid, blood, cerebrospinal fluid, or tissue biopsy. Nested PCR is the most sensitive version, but it is slow and gives no quantitative data. Diagnosing congenital cases combines amniotic fluid tests and ultrasound before birth, tests on the placenta and cord blood at birth, and neurologic and eye exams plus blood surveys in the first year.

  Most healthy people with toxoplasmosis need no treatment. Treatment is recommended for serious cases, such as people with HIV whose CD4 counts are under 200 cells/mm3. Trimethoprim/sulfamethoxazole is the drug of choice to prevent the disease, though not to treat active infection. For acute disease, doctors use pyrimethamine, an antimalarial, often paired with sulfadoxine, sold together with it as Fansidar. Clindamycin and spiramycin are other options, and spiramycin is used most often in pregnant women. Folic acid supplements accompany the combination to reduce the risk of low platelet counts, and the combination works best in people with HIV. Minocycline has seen some use as salvage therapy.

  Spiramycin is recommended in the first and early second trimesters, because it can help stop the parasite from crossing the placenta. If the fetus is already infected, doctors turn to pyrimethamine, sulfadiazine, and leucovorin in the late second and third trimesters. Amniocentesis can reveal whether the fetus is infected. Pyrimethamine is held back until after the first trimester because its antifolate effect can interfere with fetal brain formation. Newborns who receive 12 months of postnatal treatment have a low chance of sensorineural hearing loss.

  Atovaquone has been used to kill Toxoplasma cysts inside AIDS patients. Paired with clindamycin, it seemed to clear cysts best in mice. A 2012 study pointed to two endochin-like quinolones as a promising way to treat both active and latent forms. A different lead comes from Tartrolon E, a compound made by the bacterial symbiont Teredinibacter turnerae, strain T7901, which lives in the gills of shipworms, wood-eating marine mollusks. Roughly a quarter of newly approved human drugs over the last four decades came from natural sources or modified natural compounds. Tartrolon E has proven safe and highly effective against T. gondii in testing.

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• 6. Decades Of Discovery

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  Two scientists on two continents spotted the same parasite in 1908. Nicolle and Manceaux found it in Tunisia, in a North African rodent called the gundi, Ctenodactylus gundi. Splendore independently reported it in Brazil, in a rabbit. In 1909, Nicolle and Manceaux separated it from Leishmania and named it Toxoplasma gondii. The name honors the curved shape of its infectious stage, from the Greek root toxon, meaning bow.

  Janků described the first recorded case of congenital toxoplasmosis in 1923, though he never connected it to the parasite. He performed the autopsy of an 11-month-old boy who had arrived at hospital with hydrocephalus. The boy showed the classic marks of toxoplasmosis, including chorioretinitis. Janků saw a number of "sporocytes" under the microscope but did not recognize them as T. gondii.

  Sabin and Olitsky carried out the first detailed scientific analysis in 1937, using techniques developed for studying viruses. Working with laboratory monkeys and mice, they showed that T. gondii was an obligate intracellular parasite. Mice fed contaminated tissue also caught the infection, which proved the parasite could pass between animals.

  Babies Hospital in New York City reported the first human case in 1939. Wolf, Cowen, and Paige studied an infant girl delivered full-term by Caesarean section. She developed seizures and chorioretinitis in both eyes at three days old, then encephalomyelitis, and died at one month. The team isolated T. gondii from lesions in her brain tissue. Injecting brain and spinal cord samples into mice, rabbits, and rats produced encephalitis in the animals. After reviewing more cases, they concluded that the parasite caused recognizable symptoms and could pass from mother to child.

  Pinkerton and Weinman reported the first adult case in 1940, in a 22-year-old man from Peru. He had no neurological signs and died from a later bacterial infection and fever. In 1941, transmission from a pregnant woman to her baby was confirmed. Sabin and Feldman then created a dye test in 1948 that relied on how a patient's antibodies altered the staining of Toxoplasma. It remains the gold standard for identifying infection.

  Paris in 1965 supplied the proof that undercooked meat transmits the parasite. Desmonts and colleagues noticed that patients at a tuberculosis hospital who were given raw beef or horse meat as therapy saw their Toxoplasma antibodies rise by 50% per year. In 1974, Desmonts and Couvreur showed that infection in the first two trimesters does the most harm to a fetus and that timing of the mother's infection matters. Mothers who had antibodies before pregnancy did not pass the infection on, and spiramycin lowered transmission. Attention to the parasite grew in the 1970s with immune-suppressing treatment after organ and bone marrow transplants, and again with the AIDS epidemic of the 1980s.

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• 7. Animal Hosts

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  In 1942, a domestic cat in Middletown, New York became the first reported case of feline toxoplasmosis. Investigators isolated oocysts from its feces and found they could stay infectious in the environment for up to 12 months. Worldwide, an estimated 30-40% of domestic cats carry antibodies, with wide variation. A 2012 survey of 445 purebred pet cats and 45 shelter cats in Finland found 48.4%. A 2010 survey of feral cats in Giza, Egypt found 97.4%, and a Colombian survey found 89.3%. A study in Guangdong, China found just 2.1%. Local surveys in the United States range from 16% to 80%. Feral cats that hunt for food are more likely to be infected than pets. No approved feline vaccine exists, though several candidates have shown positive results in clinical trials. Control relies on preventing hunting, keeping cats off raw meat, and maintaining good litter box hygiene.

  Pigs, sheep, and goats have the highest rates of chronic infection among livestock. Worldwide, the share of pigs carrying viable parasites has been measured at 3-71.43%, and in the United States between 0% and 92.7%, depending on the herd. A 2006 report by Thiptara and colleagues described a Thai litter of three stillborn piglets and six live ones. Viable T. gondii has been found in as many as 78% of US sheep. A 2011 survey of goats intended for consumption in the United States found 53.4% had antibodies. A live attenuated vaccine called Toxovax is available to protect sheep against the effects of congenital toxoplasmosis.

  Free-ranging chickens in a US survey showed infection rates of 17-100%, depending on the farm. Chickens raised indoors in large operations are rarely infected. Poultry is not considered a major risk to humans, since chicken is usually cooked thoroughly. Cattle and buffalo usually clear the parasite within weeks, and their meat is considered low-risk. Horses are considered resistant to chronic infection. Even so, viable parasites were isolated from US horses slaughtered for export, and severe human toxoplasmosis in France has been linked to eating horse meat.

  An estimated 23% of wild swine worldwide have antibodies, with the highest rates in North America at 32% and Europe at 26%. Asia stands at 13% and South America at 5%. Higher latitudes and warmer, humid climates are associated with increased infection in wild boar, and their meat can pose a risk to people who eat it.

  Australian marsupials are especially vulnerable. Wallabies, koalas, wombats, pademelons, and small dasyurids can be killed by the parasite, and eastern barred bandicoots typically die within about three weeks of infection.

  A University of California, Davis study of dead sea otters collected from 1998 to 2004 found that toxoplasmosis caused 13% of the deaths. Proximity to freshwater outflows into the ocean was a major risk factor. Cat feces are considered the most likely ultimate source, carried by runoff or by litter flushed down toilets. The same routes may have brought the parasite to endangered Hawaiian monk seals, where infection was first noted in 2004 and has contributed to the deaths of at least four. The parasite has also been found in many whales and dolphins, including the critically endangered Māui and Hector's dolphins. A 2011 study of 161 stranded or dead Pacific Northwest marine mammals found that 42% tested positive for both T. gondii and S. neurona. Researchers Black and Massie suspect anchovies, which move from estuaries into open ocean, may help spread the disease.

  A giant panda in a Chinese zoo died in 2014 with the parasite blamed for acute gastroenteritis and respiratory disease.

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• 8. Minds And Culture

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  Infected mice and rats lose some of their natural fear of cat odor. Uninfected rodents generally avoid areas marked with cat urine or body scent, but that avoidance shrinks or vanishes in infected animals. When offered cat or mink scent, infected rodents showed a significantly stronger preference for the cat odor than uninfected controls. The change is thought to raise their chances of being eaten by cats. One mechanism involves epigenetic remodeling, in which the parasite lowers methylation of arginine vasopressin-related genes in the medial amygdala and sharply reduces predator aversion. Infected rats are more active and less wary of novelty. Infected mice travel greater distances, move faster, accelerate for longer, and pause less in new arenas. They also show lower anxiety on standard tests such as the elevated plus maze.

  Chronic infection has traditionally been regarded as symptomless in people with healthy immune systems. Some evidence suggests latent infection may subtly influence human behavior and change susceptibility to psychiatric and neurological disorders. A major caveat applies. Most studies test for antibodies after a disease or trait has already appeared, so it is unclear which came first. People with certain traits may simply be more likely to be exposed.

  Two 2012 meta-analyses found that antibody rates in people with schizophrenia were 2.7 times higher than in controls. Cautions include that antibody tests do not detect the parasite directly, that most people with schizophrenia lack the antibodies, and that publication bias may exist. Antipsychotic drugs appear to inhibit the replication of tachyzoites in cell culture. Antibody levels have also been correlated with obsessive-compulsive disorder and with suicide among people with mood disorders such as bipolar disorder, but not with major depression or dysthymia. A 2016 study of 236 people with high antibody levels found that "there was little evidence that T. gondii was related to increased risk of psychiatric disorder, poor impulse control, personality aberrations or neurocognitive impairment".

  Parkinson's disease and Alzheimer's disease have been linked to latent infection, while people with multiple sclerosis show infection rates around 15% lower than the general public. Latent infection has also been associated with a higher risk of automobile accidents, possibly through impaired psychomotor performance or a more risk-taking personality. The biologist Jaroslav Flegr is a proponent of the theory that toxoplasmosis affects human behavior.

  News organizations coined the term "crazy cat-lady syndrome" to describe findings linking the parasite to mental disorders. It draws on the stereotype of a woman who compulsively hoards and dotes on cats. A suspected link between childhood cat ownership and later schizophrenia called for more study, but a later study found that cat ownership in childhood did not predict psychotic experiences at ages 13 or 18. Researchers also found that cat ownership does not strongly raise the risk of infection in pregnant women.

  The disease has touched famous lives. Tennis player Arthur Ashe developed neurological problems from it and was later found to be HIV-positive. Actor Merritt Butrick and reality television personality Pedro Zamora both had HIV, and toxoplasmosis followed as their immune systems weakened. Prince François, Count of Clermont, a pretender to the French throne, had congenital toxoplasmosis, and his disability caused him to be overlooked in the line of succession. Actress Leslie Ash contracted it in the second month of pregnancy. Martina Navratilova experienced toxoplasmosis during the 1982 US Open. Runner Sebastian Coe caught it in 1983, probably from a cat while he trained in Italy.

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