Thursday 9 July 2015

Toxoplasmosis

Toxoplasmosis
Toxoplasma gondii tachy.jpg
T. gondii tachyzoites
Classification and external resources
SpecialtyInfectious disease
ICD-10B58
ICD-9-CM130
DiseasesDB13208
MedlinePlus000637
eMedicinemed/2294
Patient UKToxoplasmosis
MeSHD014123
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii.[1] The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid (cat) family. Infection occurs: 1.) By eating infected meat, particularly swine products. 2.) By ingesting water, soil, or food that has come into contact with infected animals' fecal matter. This is most commonly spread in feces by household cats. 3.) By transmission from infected mother to fetus during pregnancy. This is why physicians recommend that pregnant women should not clean litter boxes or eat under-cooked meat products.[2]
Up to half of the world's human population is estimated to carry a Toxoplasma infection.[3] The most recent U.S. data from 2014 indicated the rate as 22.5% nationwide and 29.2% in the northeast U.S.[4] One study claimed a seroprevalence of 75% in El Salvador.[5] Official assessment in Great Britain places the number of infections at about 350,000 a year.[6]
Toxoplasmosis is usually asymptomatic,[7][8] but during the first few weeks after exposure the infection may cause a mild, flu-like illness.[9] However, those with weakened immune systems, such as those with AIDS and pregnant women, may become seriously ill, and it can occasionally be fatal.[7] The parasite can cause encephalitis (inflammation of the brain), neurological diseases, and can affect the heart, liver, inner ears, and eyes (chorioretinitis).[10] Recent research has also linked toxoplasmosis with attention deficit hyperactivity disorder, obsessive-compulsive disorder, and schizophrenia.[11] Numerous studies found a positive correlation between latent toxoplasmosis and suicidal behavior in humans.[12][13][14]
Charles Nicolle and Louis Manceaux first described the organism in 1908, after they observed the parasites in the blood, spleen, and liver of a North African rodent, Ctenodactylus gundi. The parasite was named Toxoplasma gondii, from the Greek words τόξον (toxon, "arc" or "bow") and πλάσμα (plasma, "creature"), and after the rodent, in 1909. In 1923, Janku reported parasitic cysts in the retina of an infant who had hydrocephalus, seizures, and unilateral microphthalmia. Wolf, Cowan, and Paige (1937–1939) determined these findings represented the syndrome of severe congenital T. gondii infection.[15]


Signs and symptoms[edit]

Infection has three stages:

Acute toxoplasmosis[edit]

Acute toxoplasmosis is often asymptomatic in healthy adults.[7][8] However, symptoms may manifest and are often influenza-like: swollen lymph nodes, or muscle aches and pains that last for a month or more. Rarely will a human with a fully functioning immune system develop severe symptoms following infection. Young children and immunocompromised people, such as those with HIV/AIDS, those taking certain types of chemotherapy, or those who have recently received an organ transplant, may develop severe toxoplasmosis. This can cause damage to the brain (encephalitis) or the eyes (necrotizing retinochoroiditis).[16] Infants infected via placental transmission may be born with either of these problems, or with nasal malformations, although these complications are rare in newborns. The toxoplasmic trophozoites causing acute toxoplasmosis are referred to as Tachyzoites, and are typically found in bodily fluids.
Swollen lymph nodes are commonly found in the neck or under the chin, followed by the armpits and the groin. Swelling may occur at different times after the initial infection, persist, and recur for various times independently of antiparasitic treatment.[17] It is usually found at single sites in adults, but in children, multiple sites may be more common. Enlarged lymph nodes will resolve within one to two months in 60% of cases. However, a quarter of those affected take two to four months to return to normal, and 8% take four to six months. A substantial number (6%) do not return to normal until much later.[18]

Latent toxoplasmosis[edit]

Due to its asymptomatic nature,[7][8] it is easy for a host to become infected with Toxoplasma gondii and develop toxoplasmosis without knowing it. In most immunocompetent people, the infection enters a latent phase, during which only bradyzoites are present,[19] forming cysts in nervous and muscle tissue. Most infants who are infected while in the womb have no symptoms at birth, but may develop symptoms later in life.[20]

Cutaneous toxoplasmosis[edit]

While rare, skin lesions may occur in the acquired form of the disease, including roseola and erythema multiforme-like eruptions, prurigo-like nodules, urticaria, and maculopapular lesions. Newborns may have punctate macules, ecchymoses, or “blueberry muffin” lesions. Diagnosis of cutaneous toxoplasmosis is based on the tachyzoite form of T. gondii being found in the epidermis.[21] It is found in all levels of the epidermis, is about 6 μm by 2 μm and bow-shaped, with the nucleus being one-third of its size. It can be identified by electron microscopy or by Giemsa staining tissue where the cytoplasm shows blue, the nucleus red.[22]

Cause[edit]

The parasite’s survival is dependent on a balance between host survival and parasite proliferation.[23] This is achieved through the reduction of host’s immune response and the enhancement of the parasite’s reproductive advantage, both of which occur through the parasite’s manipulation of the host’s immune response.[23] Once the parasite T. gondii infects a normal host cell, it resists damage caused by the host’s immune system, as well as changing the host's immune processes.
In the host cell, the parasite is encapsulated in the parasitophorous vacuole (PV), whose membrane is a result of its forced entry into the cell.[9][24] The PV is both resistant to the activity of the endolysosomal system, and can take control of the host’s mitochondria and endoplasmic reticulum.[9][24]
When first invading the cell, the parasite releases ROP proteins from the bulb of the rhoptry organelle.[9] These proteins translocate to the nucleus and the surface of the PV membrane where they can activate STAT pathways to modulate the expression of cytokines at the transcriptional level, bind and inactivate PV membrane destroying IRG proteins, among other possible effects.[9][24][25] Additionally, certain strains of T. gondii are capable of secreting another protein, known as GRA15 which can activate the NF-κB pathway, to upregulate the pro-inflammatory cytokine IL-12 in the early immune response, possibly leading to the parasite’s latent phase.[9] The parasite’s ability to secrete these proteins depends on its genotype and effects its virulence.[9][25]
The parasite also exerts an effect on an anti-apoptotic mechanism, allowing the infected host cells to persist and replicate. One method of apoptosis resistance is by disrupting pro-apoptosis effector proteins, such as Bax and Bak.[26] In order to disrupt these proteins, T. gondii causes conformational changes to the proteins.[26] These conformational changes result in the inability of the proteins to be transported to various cellular compartments and initiate apoptosis events. T. gondii does not, however, cause downregulation of the pro-apoptosis effector proteins.[26]
T. gondii also has the ability to initiate autophagy of the host’s cells.[27] This leads to a decrease in healthy, uninfected cells, and consequently less host cells to attack the infected cells. Research by Wang et al finds that infected cells lead to higher levels of autophagosomes in normal and infected cells.[27] Their research reveals that T. gondii causes host cell autophagy using a calcium-dependent pathway.[27] Another study suggests that the parasite can directly affect calcium being released from calcium stores, which are important for the signalling processes of cells.[26]
The mechanisms above are very important ways in which T. gondii is able to persist in a host causing many serious problems for the host. Some limiting factors for the plasmid is that its effects on the host cells seem to thrive in a weak immune system and be dosage dependent, so a large number of T. gondii must be present per host cell to have a more severe effect.[28] The effect on the host also relies on the host having a weakened immune system. Immunocompetent individuals do not normally show severe symptoms or any at all, while fatality or severe complications can result in immunocompromised individuals.[28]
It should be noted that since the parasite can change the host’s immune response, it may also have an effect, positive or negative, on the immune response to other pathogenic threats.[23] This includes, but is not limited to, the responses to infections by Helicobacter felis, Leishmania major, or other parasites, such as Nippostrongylus brasiliensis.[23]

Transmission[edit]

Lifecycle of Toxoplasma gondii
Transmission may occur through:
  • Ingestion of raw or partly cooked meat, especially pork, lamb, or venison containing Toxoplasma cysts: Infection prevalence in countries where undercooked meat is traditionally eaten has been related to this transmission method. Tissue cysts may also be ingested during hand-to-mouth contact after handling undercooked meat, or from using knives, utensils, or cutting boards contaminated by raw meat.[29]
  • Ingestion of unwashed fruits or vegetables that have been in contact with contaminated soil containing infected cat feces.[30]
  • Ingestion of contaminated cat feces: This can occur through hand-to-mouth contact following gardening, cleaning a cat's litter box, contact with children's sandpits; the parasite can survive in the environment for over a year.[31]
  • Acquiring congenital infection through the placenta.[16]
Cats excrete the pathogen in their feces for a number of weeks after contracting the disease, generally by eating an infected rodent. Even then, cat feces are not generally contagious for the first day or two after excretion, after which the cyst 'ripens' and becomes potentially pathogenic.[32]

Pregnancy precautions[edit]

Congenital toxoplasmosis is a special form in which an unborn fetus is infected via the placenta.[33] A positive antibody titer indicates previous exposure and immunity, and largely ensures the unborn fetus' safety. A simple blood draw at the first prenatal doctor visit can determine whether or not a woman has had previous exposure and therefore whether or not she is at risk. If a woman receives her first exposure to T. gondii while pregnant, the fetus is at particular risk.
Pregnant women should avoid handling raw meat, drinking raw milk (especially goat milk) and be advised to not eat raw or undercooked meat regardless of type.[34] Because of the obvious relationship between Toxoplasma and cats it is also often advised to avoid exposure to cat feces, and refrain from gardening (cat feces are common in garden soil) or at least wear gloves when so engaged.[34] Most cats are not actively shedding oocysts since they get infected in the first 6 months of their life. They shed oocysts for only a short period of time (1–2 weeks.)[35] However, these oocysts get buried in the soil, sporulate and remain infectious for periods ranging from several months to more than a year.[34] Numerous studies have shown living in a household with a cat is not a significant risk factor for T. gondii infection,[34][36][37] though living with several kittens has some significance.[38]
For pregnant women with negative antibody titers, indicating no previous exposure to T. gondii, serology testing as frequent as monthly is advisable as treatment during pregnancy for those women exposed to T. gondii for the first time decreases dramatically the risk of passing the parasite to the fetus.
Despite these risks, pregnant women are not routinely screened for toxoplasmosis in most countries (Portugal,[39] France,[40] Austria,[40] Uruguay,[41] and Italy[42] being the exceptions) for reasons of cost-effectiveness and the high number of false positives generated. As invasive prenatal testing incurs some risk to the fetus (18.5 pregnancy losses per toxoplasmosis case prevented),[40] postnatal or neonatal screening is preferred. The exceptions are cases where fetal abnormalities are noted, and thus screening can be targeted.[40]
Some regional screening programmes operate in Germany, Switzerland and Belgium.[42]
Treatment is very important for recently infected pregnant women, to prevent infection of the fetus. Since a baby's immune system does not develop fully for the first year of life, and the resilient cysts that form throughout the body are very difficult to eradicate with antiprotozoans, an infection can be very serious in the young.
In 2006, a Czech research team[43] discovered women with high levels of toxoplasmosis antibodies were significantly more likely to have baby boys than baby girls. In most populations, the birth rate is around 51% boys, but women infected with T. gondii had up to a 72% chance of a boy.[44][45] In mice, the sex ratio was higher in early latent toxoplasmosis and lower in later latent toxoplasmosis.[45]

Rodent behavior[edit]

Infection with T. gondii has been shown to alter the behavior of mice and rats in ways thought to increase the rodents’ chances of being preyed upon by cats.[46][47][48] Infected rodents show a reduction in their innate aversion to cat odors; while uninfected mice and rats will generally avoid areas marked with cat urine or with cat body odor, this avoidance is reduced or eliminated in infected animals.[46][48][49] Moreover, some evidence suggests this loss of aversion may be specific to feline odors: when given a choice between two predator odors (cat or mink), infected rodents show a significantly stronger preference to cat odors than do uninfected controls.[50][51]
In rodents, T. gondii–induced behavioral changes occur through epigenetic remodeling in neurons associated observed behaviors;[52][53] for example, it modifies epigenetic methylation to induce hypomethylation of arginine vasopressin-related genes in the medial amygdala to greatly decrease predator aversion.[52][53] Similar epigenetically-induced behavioral changes have also been observed in mouse models of addiction, where changes in the expression of histone-modifying enzymes via gene knockout or enzyme inhibition in specific neurons produced alterations in drug-related behaviors.[54][55][56] Widespread histone-lysine acetylation in cortical astrocytes appears to be another epigenetic mechanism employed by T. gondii.[57][58]
T. gondii-infected rodents show a number of behavioral changes beyond altered responses to cat odors. Rats infected with the parasite show increased levels of activity and decreased neophobic behavior.[47][59] Similarly, infected mice show alterations in patterns of locomotion and exploratory behavior during experimental tests. These patterns include traveling greater distances, moving at higher speeds, accelerating for longer periods of time, and showing a decreased pause-time when placed in new arenas.[60] Infected rodents have also been shown to have differences in traditional measures of anxiety, such as elevated plus mazes, open field arenas, and social interaction tests.[60][61]

Diagnosis[edit]

Diagnosis of toxoplasmosis in humans is made by biological, serological, histological, or molecular methods, or by some combination of the above.[35] Toxoplasmosis can be difficult to distinguish from primary central nervous system lymphoma. It mimics several other infectious diseases so clinical signs are non-specific and are not sufficiently characteristic for a definite diagnosis. As a result, the diagnosis is made by a trial of therapy (pyrimethamine, sulfadiazine, and folinic acid (USAN: leucovorin)), followed by a brain biopsy if the drugs produce no effect clinically and no improvement on repeat imaging.
Detection of T. gondii in human blood samples may also be achieved by using the polymerase chain reaction.[62] Inactive cysts may exist in a host that would evade detection.
Several serological procedures are available for the detection of T. gondii antibody in patients, which may aid diagnosis; these include the Sabin–Feldman dye test (DT), the indirect hemagglutination assay, the indirect fluorescent antibody assay (IFA), the direct agglutination test, the latex agglutination test (LAT), the enzyme-linked immunosorbent assay (ELISA), and the immunosorbent agglutination assay test (IAAT). The IFA, IAAT and ELISA have been modified to detect immunoglobulin M (IgM) antibodies.[35]
IgG antibody
The most commonly used tests for the measurement of IgG antibody are the DT, the ELISA, the IFA, and the modified direct agglutination test.[63] These tests reveal that IgG antibodies usually appear within 1–2 weeks of acquisition of the infection, peak within 1–2 months, decline at various rates, and usually persist for life.[63]
Acute infections can be differentiated from chronic infections using the “differential” agglutination test (also known as the AC/HS test), which is best used in combination with a panel of other tests such as the TSP.[63] The AC/HS test results when parasites are fixed for use in the agglutination test with two different compounds (i.e., acetone and formalin). The different antigenic preparations vary in their ability to recognize sera obtained during the acute and chronic stages of the infection.[63]
IgM antibody
The most commonly used tests for the measurement of IgM antibody are double-sandwich or capture IgM-ELISA kits, the IFA test, and the immunosorbent agglutination assay (IgM-ISAGA). Commercial test kits often have low specificity, and the reported results are frequently misinterpreted.[64] The IgM antibodies appear sooner after infection than the IgG antibodies and disappear faster than IgG antibodies after recovery.[35] In most cases, T. gondii-specific IgM antibodies are detected initially in patients with recently acquired primary infection, but these titers become negative within a few months.[63] However, in some patients, positive T. gondii-specific IgM titers can still be observed during the chronic phase of infection.[63]
Congenital toxoplasmosis
A whole set of recommendations applies for the diagnosis of congenital toxoplasmosis: i) prenatal diagnosis based on molecular testing of amniotic fluid and ultrasound examinations; ii) molecular testing of placenta and cord blood, comparative mother-child serologic tests and a clinical examination at birth; iii) neurologic and ophthalmologic examinations and a serologic survey during the first year of life.[33]
Even though diagnosis of toxoplasmosis heavily relies on serological detection of specific anti-Toxoplasma immunoglobulin, serological testing does have its limitations. For example, it may fail to detect the active phase of T. gondii infection because the specific anti-Toxoplasma IgG or IgM may not be produced until after several weeks of parasitemia. As a result, a pregnant mother might test negative during the active phase of T. gondii infection leading to the undetection of congenital toxoplasmosis of a fetus.[65] Also, the test may fail to detect T. gondii infections in immunocompromised patients because the titers of specific anti-Toxoplasma IgG or IgM may fail to rise in this type of patient.
A lot of PCR-based techniques have been developed for the diagnosis of toxoplasmosis using various clinical specimens, including amniotic fluid, blood, cerebrospinal fluid, and tissue biopsy. The most sensitive method among the PCR-based techniques is nested PCR followed by hybridization of PCR products.[65] The major downside to these techniques is that they are time consuming and do not provide quantitative data.[65]
Real-time PCR is useful in pathogen detection, gene expression and regulation, and allelic discrimination. This PCR technique utilizes the 5' nuclease activity of Taq DNA polymerase to cleave a nonextendible, fluorescence-labeled hybridization probe during the extension phase of PCR.[65] A second fluorescent dye, e.g., 6-carboxy-tetramethyl-rhodamine, quenches the fluorescence of the intact probe.[65] The nuclease cleavage of the hybridization probe during the PCR releases the effect of quenching resulting in an increase of fluorescence proportional to the amount of PCR product, which can be monitored by a sequence detector.[65]
Toxoplasmosis cannot be detected with immunostaining. Lymph nodes affected by Toxoplasma have characteristic changes, including poorly demarcated reactivegerminal centers, clusters of monocytoid B cells, and scattered epithelioid histiocytes.

Treatment[edit]

Treatment is often only recommended for people with serious health problems, such as people with HIV whose CD4 counts are under 200, because the disease is most serious when one's immune system is weak. Trimethoprim/sulfamethoxazole is the drug of choice to prevent toxoplasmosis, but not for treating active disease. A new study (May 2012) shows a promising new way to treat the active and latent form of this disease using two endochin-like quinolones.[66]

Acute[edit]

The medications prescribed for acute toxoplasmosis are the following:
(other antibiotics, such as minocycline, have seen some use as a salvage therapy).

Latent[edit]

In people with latent toxoplasmosis, the cysts are immune to these treatments, as the antibiotics do not reach the bradyzoites in sufficient concentration.
The medications prescribed for latent toxoplasmosis are:

Epidemiology[edit]

T. gondii infections occur throughout the world, although infection rates differ significantly by country.[69] For women of childbearing age, a survey of 99 studies within 44 countries found the areas of highest prevalence are within Latin America (about 50–80%), parts of Eastern and Central Europe (about 20–60%), the Middle East (about 30-50%), parts of Southeast Asia (about 20–60%), and parts of Africa (about 20–55%).[69]
In the United States, data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004 found 9.0% of US-born persons 12–49 years of age were seropositive for IgG antibodies against T. gondii, down from 14.1% as measured in the NHANES 1988–1994.[70] In the 1999–2004 survey, 7.7% of US-born and 28.1% of foreign-born women 15–44 years of age were T. gondii seropositive.[70] A trend of decreasing seroprevalence has been observed by numerous studies in the United States and many European countries.[69]
The protist responsible for Toxoplasmosis is T. gondii. There are three major types of T. gondii responsible for the patterns of Toxoplasmosis throughout the world. There is type I, II, and III. These three types of T. gondii have differing effects on certain hosts, mainly mice and humans due to their variation in genotypes.[45]
  • Type I: virulent in mice and humans, seen in AIDS patients.
  • Type II: non-virulent in mice, virulent in humans (mostly Europe and North America), seen in AIDS patients.
  • Type III: non-virulent in mice, virulent mainly in animals but seen to a lesser degree in humans as well.
Current serotyping techniques can only separate type I or III from type II parasites.[71]
Because the parasite poses a particular threat to fetuses when it is contracted during pregnancy,[72] much of the global epidemiological data regarding T. gondii comes from seropositivity tests in women of childbearing age. Seropositivity tests look for the presence of antibodies against T. gondii in blood, so while seropositivity guarantees one has been exposed to the parasite, it does not necessarily guarantee one is chronically infected.[73]

History[edit]

Toxoplasma gondii was first described in 1908 by Nicolle and Manceaux in Tunisia, and independently by Splendore in Brazil.[74] Splendore reported the protozoan in a rabbit, while Nicolle and Manceaux identified it in a North African rodent, the gundi (Ctenodactylus gundi).[75] In 1909 Nicolle and Manceaux differentiated the protozoan from Leishmania.[74] Nicolle and Manceaux then named it Toxoplasma gondii after the curved shape of its infectious stage (Greek root ‘toxon’= bow).[74]
The first recorded case of congenital toxoplasmosis was in 1923, but it was not identified as caused by T. gondii.[75] Janků (1923) described in detail the autopsy results of an 11-month-old boy who had presented to hospital with hydrocephalus. The boy had classic marks of toxoplasmosis including chorioretinitis (inflammation of the choroid and retina of the eye).[75] Histology revealed a number of “sporocytes”, though Janků did not identify these as T. gondii.[75]
It was not until 1937 that the first detailed scientific analysis of T. gondii took place using techniques previously developed for analyzing viruses.[74] In 1937 Sabin and Olitsky analyzed T. gondii in laboratory monkeys and mice. Sabin and Olitsky showed that T. gondii was an obligate intracellular parasite and that mice fed T. gondii-contaminated tissue also contracted the infection.[74] Thus Sabin and Olitsky demonstrated T. gondii as a pathogen transmissible between animals.
T. gondii was first identified as a human pathogen in 1939.[74] Wolf, Cowen and Paige identified T. gondii infection in an infant girl delivered full-term by Caesarean section.[75] The infant developed seizures and had chorioretinitis in both eyes at three days. The infant then developed encephalomyelitis and died at one month of age. Wolf, Cowen and Paige isolated T. gondii from brain tissue lesions. Intracranial injection of brain and spinal cord samples into mice, rabbits and rats produced encephalitis in the animals.[74] Wolf, Cowen and Page reviewed additional cases and concluded that T. gondii produced recognizable symptoms and could be transmitted from mother to child.[75]
The first adult case of toxoplasmosis was reported in 1940 with no neurological signs. Pinkerton and Weinman reported the presence of Toxoplasma in a 22-year-old man from Peru who died from a subsequent bacterial infection and fever.[75]
In 1948, a serological dye test was created by Sabin and Feldman based on the ability of the patient’s antibodies to alter staining of Toxoplasma.[74][76] The Sabin Feldman Dye Test is now the gold standard for identifying Toxoplasma infection.[74]
Transmission of Toxoplasma by eating raw or undercooked meat was demonstrated by Desmonts et al. in 1965 Paris.[74] Desmonts observed that the therapeutic consumption of raw beef or horse meat in a tuberculosis hospital was associated with a 50% per year increase in Toxoplasma antibodies.[74] This means that more T. gondii was being transmitted through the raw meat.
In 1974, Desmonts and Couvreur showed that infection during the first two trimesters produces most harm to the fetus, that transmission depended on when mothers were infected during pregnancy, that mothers with antibodies before pregnancy did not transmit the infection to the fetus, and that spiramycin lowered the transmission to the fetus.[75]
Toxoplasma gained more attention in the 1970s with the rise of immune-suppressant treatment given after organ or bone marrow transplants and the AIDS epidemic of the 1980s.[74] Patients with lowered immune system function are much more susceptible to disease.

Society and culture[edit]

"Crazy cat lady syndrome"[edit]

"Crazy cat lady syndrome" is a term coined by news organizations to describe scientific findings that link the parasite Toxoplasma gondii to several mental disorders and behavioral problems.[77][78][79][80][81] Although researches found that cat ownership does not strongly increase the risk of T. gondii infection on pregnant women,[82][83] the strong correlation between the cat ownership on childhood and later development of schizophrenia suggests it is indeed a risk factor for children.[84] The term crazy cat lady syndrome draws on both stereotype and popular cultural reference. It was originated as instances of the aforementioned afflictions were noted amongst the populace. Cat lady is a cultural stereotype of a woman who compulsively hoards cats and dotes upon them, often a spinster. Jaroslav Flegr (biologist) is a proponent of the theory that toxoplasmosis affects human behavior.[85][86]

Notable cases[edit]

In popular culture[edit]

  • In The Fallen (2013), book five of Charlie Higson's post-apocalyptic series The Enemy, Skinman explains to Blue that the "Nightmare Bug" that's afflicted the adults and deformed the children of the scientists who originally contracted it is akin to toxoplasmosis.[94] This explanation recalls Maxie's story about her despondent friend Lila's having become suicidal following the deaths of her cat and kitten, who were suffering from cat flu,[95] and it implies possible contributions to the transformations of such characters as Paul, who had been mourning his sister's death and whose personality changed when he began exhibiting flu-like symptoms,[96] after being bitten by a diseased adult;[97] and the undue risk-taking by such characters as Jake[98] (who like the other children, had lost friends and family and had to fight and kill to survive). Skinman's explanation also recalls cat-lover Frederique Morel (first encountered in The Dead (2010)), who remained despondent after her father's death and eventually transformed[99] while some others who reached her age (e.g., Blue[100]) did not.
  • In 1993 novel Trainspotting, character Matty dies of toxoplasmosis exacerbated by AIDS. For the film, the character who dies of toxoplasmosis is instead Tommy.

Other animals[edit]

T. gondii infects virtually all warm-blooded animals; these tachyzoites were found in a bird[101]
Although T. gondii has the capability of infecting virtually all warm-blooded animals, susceptibility and rates of infection vary widely between different genera and species.[102] Rates of infection in populations of the same species can also vary widely due to differences in location, diet, and other factors.
Although infection with T. gondii has been noted in several species of Asian primates, seroprevalence of T. gondii antibodies was found for the first time in toque macaques (Macaca sinica) that are endemic to the island of Sri Lanka.[103]

Livestock[edit]

Among livestock, pigs, sheep[104] and goats have the highest rates of chronic T. gondii infection.[105] The prevalence of T. gondii in meat-producing animals varies widely both within and between countries,[105] and rates of infection have been shown to be dramatically influenced by varying farming and management practices.[8] For instance, animals kept outdoors or in free-ranging environments are more at risk of infection than animals raised indoors or in commercial confinement operations.[8][106]
In the United States, the percentage of pigs harboring viable parasites has been measured (via bioassay in mice or cats) to be as high as 92.7% and as low as 0%, depending on the farm or herd.[106] Surveys of seroprevalence (T. gondii antibodies in blood) are more common, and such measurements are indicative of the high relative seroprevalence in pigs across the world.[107] Along with pigs, sheep and goats are among the most commonly infected livestock of epidemiological significance for human infection.[105] Prevalence of viable T. gondii in sheep tissue has been measured (via bioassay) to be as high as 78% in the United States,[108] and a 2011 survey of goats intended for consumption in the United States found a seroprevalence of 53.4%.[109]
Due to a lack of exposure to the outdoors, chickens raised in large-scale indoor confinement operations are not commonly infected with T. gondii.[8] Free-ranging or backyard-raised chickens are much more commonly infected.[8] A survey of free-ranging chickens in the United States found its prevalence to be 17%–100%, depending on the farm.[110] Because chicken meat is generally cooked thoroughly before consumption, poultry is not generally considered to be a significant risk factor for human T. gondii infection.[111]
Although cattle and buffalo can be infected with T. gondii, the parasite is generally eliminated or reduced to undetectable levels within a few weeks following exposure.[8] Tissue cysts are rarely present in buffalo meat or beef, and meat from these animals is considered to be low-risk for harboring viable parasites.[105][106]
Horses are considered resistant to chronic T. gondii infection.[8] However, viable cells have been isolated from US horses slaughtered for export, and severe human toxoplasmosis in France has been epidemiologically linked to the consumption of horse meat.[106]

Domestic cats[edit]

The seroprevalence of T. gondii in domestic cats, worldwide, has been estimated to be around 30–40%.[112] In the United States, no official national estimate has been made, but local surveys have shown levels varied between 16% and 80%.[112] A 2012 survey of 445 purebred pet cats and 45 shelter cats in Finland found an overall seroprevalence of 48.4%.[113] A 2010 survey of feral cats from Giza, Egypt, found an overall seroprevalence of 97.4%.[114]
T. gondii infection rates in domestic cats vary widely depending on the cats' diets and lifestyles.[115] Feral cats that hunt for their food are more likely to be infected than domestic cats. The prevalence of T. gondii in cat populations depends on the availability of infected birds and small mammals,[116] but often this prey is abundant.
Most infected cats will shed oocysts only once in their lifetimes, for a period of about one to two weeks.[112] Although this period of shedding is quite transient, millions of oocysts can be shed, with each oocyst capable of spreading and surviving for months.[112] An estimated 1% of cats at any given time are actively shedding oocysts.[8]

Marine mammals[edit]

A University of California, Davis study of dead sea otters collected from 1998 to 2004 found toxoplasmosis was the cause of death for 13% of the animals.[117] Proximity to freshwater outflows into the ocean was a major risk factor. Ingestion of oocysts from cat feces is considered to be the most likely ultimate source.[118] Surface runoff containing wild cat feces and litter from domestic cats flushed down toilets are possible sources of oocysts.[119] The parasites have been found in dolphins and whales.[120] Researchers Black and Massie believe anchovies, which travel from estuaries into the open ocean, may be helping to spread the disease.

Research[edit]

Chronic infection with T. gondii has traditionally been considered asymptomatic in immunocompetent human hosts. However, accumulating evidence suggests latent infection may subtly influence a range of human behaviors and tendencies, and infection may alter the susceptibility to or intensity of a number of affective, psychiatric, or neurological disorders.[121]
Micrograph of a lymph node showing the characteristic changes of toxoplasmosis (scattered epithelioid histiocytes (pale cells), monocytoid cells (top-center of image), large germinal centers (left of image)) H&E stain
Latent T. gondii infection in humans has been associated with a higher incidence of automobile accidents, potentially due to impaired psychomotor performance or enhanced risk-taking personality profiles.[121] Moreover, correlations have been found between positive antibody titers to T. gondii and OCD, Parkinson's disease, Alzheimer's disease, suicide in people with mood disorders, and bipolar disorder.[121] Positive antibody titers to T. gondii have been shown to be not correlative with major depression or dysthymia.[122] Although there is a correlation between T. gondii infection and many psychological disorders, scientists are still trying to find the cause on a cellular level.

Schizophrenia[edit]

The most substantial body of evidence linking T. gondii to a neurological disorder involves the potential association between schizophrenia and infection with the parasite.[46][123] A 2007 meta-analysis, including 23 studies, found the prevalence of antibodies to T.gondii in schizophrenia patients was significantly higher than that in control populations, with a combined odds ratio of 2.73 (95% CI 2.10-3.60). These results suggest individuals with schizophrenia have an increased prevalence of antibodies to T.gondii compared to the general population.[123] Furthermore, this odds ratio suggests a stronger association between schizophrenia and T.gondii antibodies than any human gene identified in schizophrenia genome-wide association studies (OR from 1.6-1.8)[123][124] In 2012, an updated meta-analysis included 15 additional studies, for a total of 38 studies that together show a positive correlation between T.gondii antibody titres and schizophrenia with a reconfirmed combined odds ratio of 2.73 (95% CI 2.21-3.28).[125] T.gondii antibody positivity was therefore considered an intermediate risk factor in relation to other known schizophrenia risk factors.[125]
While the vast majority of these studies tested people already diagnosed with schizophrenia for T. gondii antibodies, significant associations between T. gondii and schizophrenia have been found prior to the onset of schizophrenia disease symptoms.[46] For example, a study of 180 military personnel who were demilitarized due to a schizophrenia diagnosis found significantly increased levels of T.gondii antibodies detected in frozen blood samples collected prior to their schizophrenia diagnosis.[126] Additionally, among the 23 studies included in the 2007 meta-analysis, seven investigated T.gondii antibody levels associated with first-episode schizophrenia for which the combined odds ratio was 2.54, which was not significantly different than the odds ratio for studies including all schizophrenia patients (OR=2.79).[123]
In order to explain the observed correlation between toxoplasmosis and schizophrenia, studies have been conducted in search for evidence of a causal role for T.gondii in triggering schizophrenia. One study used voxel-based morphometry to measure grey matter volume of brain areas in patients with schizophrenia.[127] Whereas previous studies have determined that patients with schizophrenia have reduced overall grey matter volume in select brain areas compared to healthy controls, the above-mentioned study determined that grey matter reductions were significantly greater in T.gondii seropositive schizophrenia patients compared to T.gondii seronegative schizophrenia patients. Additionally, grey matter volume did not differ significantly in relation to T.gondii status in patients without schizophrenia.[127] Furthermore, one study compared differences in schizophrenia onset and severity between toxoplasmosis-infected and toxoplasmosis-free patients and found toxoplasmosis-infected schizophrenia patients show more severe psychosis symptoms compared to toxoplasmosis-free patients.[128] This same study found that while the average onset of schizophrenia is approximately equal for toxoplasmosis seronegative males and females, the average onset of schizophrenia was approximately 3 years later in toxoplasmosis-infected females compared to males.[128] Studies attempting to explain this sex-dependent disparity in schizophrenia onset have suggested it can be accounted for by a previously characterized second peak of T.gondii infection incidence occurring from ages 25–30 observed in females only.[129][130] Additionally, patients with schizophrenia and T. gondii antibodies show a higher mortality rate than schizophrenics testing seronegative.[45] Also, minocycline, an antibiotic capable of passing the blood-brain barrier used for treating toxoplasmosis, has been found to help the symptoms of schizophrenia.[131]
Although a physiological mechanism supporting the association between schizophrenia and T.gondii infection is largely unknown, studies have attempted to discern a molecular mechanism to explain the correlation.[130] A T.gondii genome sequencing study found two genes encoding for an enzyme with significant homology to mammalian tyrosine hydroxylase, an enzyme involved in the conversion of tyrosine to the known dopamine precursor, L-DOPA [132] Schizophrenia has long been linked to dopamine dysregulation.[133] Therefore, this parasite-synthesized enzyme may contribute to the behavioral changes observed in toxoplasmosis by altering the production of dopamine, a neurotransmitter involved in mood, sociability, attention, motivation, and sleep patterns. Animal studies have shown significant tyrosine hydroxylase activity and increased dopamine levels within T.gondii cysts.[134] Additionally, studies have suggested that interferon gamma (IFNγ ), secreted in response to T. gondii infection, induces astrocytes to produce indoleamine 2,3-dioxygenase (IDO).[135] Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme involved in a pathway that catabolizes tryptophan to kynurenic acid (KYNA), which is a known antagonist of glutamate NMDA receptors thought to play an important role in schizophrenia.[136]

Traffic accidents[edit]

In addition to a correlation with psychological disorders such as OCD, schizophrenia, and depression, T. gondii can also lead to infected people having a higher risk of being in a car accident than uninfected individuals.[45] A study in the Czech Republic found that latent toxoplasmosis patients were involved in accidents 2.65 times more often than people without toxoplasmosis infection.[45] The risk also increased with significantly higher amounts of T. gondii antibodies in the host cells.[45]

Limitations of correlation analysis[edit]

In most of the current studies where positive correlations have been found between T. gondii antibody titers and certain behavioral traits or neurological disorders, T. gondii seropositivity tests are conducted after the onset of the examined disease or behavioral trait; that is, it is often unclear whether infection with the parasite increases the chances of having a certain trait or disorder, or if having a certain trait or disorder increases the chances of becoming infected with the parasite.[137] Groups of individuals with certain behavioral traits or neurological disorders may share certain behavioral tendencies that increase the likelihood of exposure to and infection with T. gondii; as a result, it is difficult to confirm causal relationships between T. gondii infections and associated neurological disorders or behavioral traits.[137] Provided there is in fact an etiological link between T. gondii and schizophrenia, studies have yet to determine why some individuals with latent toxoplasmosis develop schizophrenia while others do not, however, some plausible explanations include differing genetic susceptibility, parasite strain differences, and differences in the route of the acquired T.gondii infection.[123]

See also[edit]

References[edit]

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  135. Jump up ^ Silva, NM; Rodrigues, CV; Santoro, MM; Reis, LF; Varez-Leite, JI; Gazzinelli, RT (2002). "Expression of indoleamine 2,3-dioxygenase, tryptophan degradation, and kynurenine formation during in vivo infection with Toxoplasma gondii : induction by endogenous gamma interferon and requirement of interferon regulatory factor 1". Infection and Immunity 70: 859–869. doi:10.1128/IAI.70.2.859-868.2002. 
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