Toxoplasmosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

Toxoplasma gondii is a protozoan parasite that infects most species of warm blooded animals, including humans, causing the disease toxoplasmosis. Members of the cat family (Felidae) are the only known definitive hosts for the sexual stages of T. gondii and thus are the main reservoirs of infection. Cats become infected with T. gondii by carnivorism . After tissue cysts or oocysts are ingested by the cat, viable organisms are released and invade epithelial cells of the small intestine where they undergo an asexual followed by a sexual cycle and then form oocysts, which are excreted. The unsporulated oocyst takes 1 to 5 days after excretion to sporulate (become infective). Although cats shed oocysts for only 1 to 2 weeks, large numbers may be shed. Oocysts can survive in the environment for several months and are remarkably resistant to disinfectants, freezing, and drying, but are killed by heating to 70°C for 10 minutes.

Pathophysiology

Toxoplasma gondii is a protozoan parasite that infects most species of warm blooded animals, including humans, causing the disease toxoplasmosis. Members of the cat family (Felidae) are the only known definitive hosts for the sexual stages of T. gondii and thus are the main reservoirs of infection. Cats become infected with T. gondii by carnivorism . After tissue cysts or oocysts are ingested by the cat, viable organisms are released and invade epithelial cells of the small intestine where they undergo an asexual followed by a sexual cycle and then form oocysts, which are excreted. The unsporulated oocyst takes 1 to 5 days after excretion to sporulate (become infective). Although cats shed oocysts for only 1 to 2 weeks, large numbers may be shed. Oocysts can survive in the environment for several months and are remarkably resistant to disinfectants, freezing, and drying, but are killed by heating to 70°C for 10 minutes.

Life cycle

Life cycle of Toxoplasma gondii

• The only known definitive hosts for Toxoplasma gondii are members of family Felidae (domestic cats and their relatives).
• T gondii has 2 distinct life cycles.
• The sexual cycle occurs only in cats, the definitive host.
• The asexual cycle occurs in other mammals (including humans) and various strains of birds.
• Unsporulated oocysts are shed in the cat’s feces.
• Although oocysts are usually only shed for 1-2 weeks, large numbers may be shed.
• Oocysts take 1-5 days to sporulate in the environment and become infective.
• Intermediate hosts in nature (including birds and rodents) become infected after ingesting soil, water or plant material contaminated with oocysts.
• Oocysts transform into tachyzoites shortly after ingestion.
• These tachyzoites localize in neural and muscle tissue and develop into tissue cyst bradyzoites.
• Cats become infected after consuming intermediate hosts harboring tissue cysts.
• Cats may also become infected directly by ingestion of sporulated oocysts.
• Animals bred for human consumption and wild game may also become infected with tissue cysts after ingestion of sporulated oocysts in the environment.
• Humans can become infected by any of several routes:
  • Eating undercooked meat of animals harboring tissue cysts.
  • Consuming food or water contaminated with cat feces or by contaminated environmental samples (such as fecal-contaminated soil or changing the litter box of a pet cat).
  • Blood transfusion or organ transplantation.
  • Transplacentally from mother to fetus.
• In the human host, the parasites form tissue cysts, most commonly in skeletal muscle, myocardium, brain, and eyes; these cysts may remain throughout the life of the host.
• Diagnosis is usually achieved by serology, although tissue cysts may be observed in stained biopsy specimens.
• Diagnosis of congenital infections can be achieved by detecting T. gondii DNA in amniotic fluid using molecular methods such as PCR .

Pathogenesis

Transmission

• Infection can occur by ingestion of oocysts following the handling of contaminated soil or cat litter or through the consumption of contaminated water or food sources (eg, unwashed garden vegetables).
• Transmission of tachyzoites to the fetus can occur via the placenta following primary maternal infection.
• Rarely, infection by tachyzoites occurs from ingestion of unpasteurized milk or by direct entry into the bloodstream through a blood transfusion or laboratory accident.
• Transmission can also occur via ingestion of tissue cysts (bradyzoites) in undercooked or uncooked meat or through transplantation of an organ that contains tissue cysts.

Dissemination

• They are transported via the lymphatics and are disseminated hematogenously throughout the tissues.

Incubation Period

The time between exposure to the parasite and symptom development is 1 - 2 weeks.

Infective stages of the Parasite

The three infective stages of T. gondii include:

• Tachyzoite: It is the rapidly dividing and invasive form and can invade any vertebrate cell type
• Bradyzoite: These are the result of conversion from tachyzoites, they are slowly diving form and are present as tissue cysts, which can remain in the host throughout the lifetime in the muscles.
• Sporozoite: It is the environmental form present in the oocysts

Mechanism of cell Invasion

• The initial step of invasion is attachment of the tachyzoite to the host cell membrane. A set of proteins help in the adherence and penetration of the host cell membrane, these proteins also enhance the growth and virulence of the parasite.
• In the host cell the parasite forms a vacuole where it divides for 6 to 9 cycles after which the parasites are released into the circulation. It is an active process dependent on the increase in intracellular calcium stores.

Pathogenesis of Vertical Transmission

• Acute infection with tachyzoites in the blood stream during pregnancy, a possibility of transplacental infection is present.
• The tachyzoites colonize in the placenta and can cross the barrier to reach the fetus in 30% of cases leading to the disease.
• The frequency of transmission of the tachyzoites to the fetus is related to the gestational age, with low transmission rates in the first trimester (10-15%) and highest transmission rates in the third trimester (60-90%). However the disease is more severe if the infection is acquired early in the pregnancy.
• The factors influencing the transfer of tachyzoites to the fetus is not well understood.

Associated Conditions

The parasite itself can cause various effects on the host body, some of which are not fully understood.

Reproductive changes

• A recent study has indicated Toxoplasmosis correlates strongly with an increase in boy births in humans.

• According to the researchers, depending on the antibody concentration, the probability of the birth of a boy can increase up to a value of 0.72 ... which means that for every 260 boys born, 100 girls are born.
• The study also notes a mean rate of 0.60 to 0.65 (as opposed to the normal 0.51) for Toxoplasma-positive mothers.

Behavioral changes

• It has been found that the parasite has the ability to change the behavior of its host
• The mechanism for this change is not completely understood, but there is evidence that toxoplasmosis infection raises dopamine levels.
• The behaviors observed, if caused by the parasite, are likely due to infection and low-grade encephalitis, which is marked by the presence of cysts in the brain, which may produce or induce production of a neurotransmitter, possibly dopamine, therefore acting similarly to dopamine reuptake inhibitor type antidepressants and stimulants.
  • Decreased novelty-seeking behaviour
  • Slower reactions
  • Lower rule-consciousness and jealousy (in men)
  • More warmth and conscientiousness (in women)
• Studies have found that toxoplasmosis is associated with an increased car accident rate, roughly doubling or tripling the chance of an accident relative to uninfected people.
• This may be due to the slowed reaction times that are associated with infection. "If our data are true then about a million people a year die just because they are infected with toxoplasma," the researcher Jaroslav Flegr told The Guardian.
• The data shows that the risk decreases with time after infection, but is not due to age.
• However there is also evidence of a delayed effect which increases reaction times.
• Other studies suggest that the parasite may influence personality. There are claims of toxoplasma causing antisocial attitudes in men and promiscuity.
• Even signs of higher intelligence in women, and greater susceptibility to schizophrenia and manic depression in all infected persons.

Intelligence Quotient

• The study suggests that male carriers have lower intelligence quotient(IQ)s, a tendency to achieve a lower level of education and have shorter attention spans, a greater likelihood of breaking rules and taking risks, and are more independent, anti-social, suspicious, jealous and morose.
• It also suggests that these men are deemed less attractive to women.
• Women carriers are suggested to be more outgoing, friendly, more promiscuous, and are considered more attractive to men compared with non-infected controls.

Schizophrenia

• The possibility that toxoplasmosis is one cause of schizophrenia has been studied by scientists since at least 1953.
• These studies had attracted little attention from U.S. researchers until they were publicized through the work of prominent psychiatrist and advocate E. Fuller Torrey.
• In 2003, Torrey published a review of this literature, reporting that almost all the studies had found that schizophrenics have elevated rates of toxoplasma infection.
• A 2006 paper has even suggested that prevalence of toxoplasmosis has large-scale effects on national culture.
• These types of studies are suggestive but cannot confirm a causal relationship (because of the possibility, for example, that schizophrenia increases the likelihood of toxoplasma infection rather than the other way around).
• Acute Toxoplasma infection sometimes leads to psychotic symptoms not unlike schizophrenia.
• Some anti-psychotic medications that are used to treat schizophrenia, such as Haloperidol, also stop the growth of Toxoplasma in cell cultures.
• Several studies have found significantly higher levels of Toxoplasma antibodies in schizophrenia patients compared to the general population.
• Toxoplasma infection causes damage to astrocytes in the brain, and such damage is also seen in schizophrenia.

Gross Pathology

• T.gondii has tropism for central nervous system and mostly affects the brain and eye. Areas of necrosis and granulomatous lesions in the brain can be demonstrated on autopsy.

Microscopic Pathology

• In patients with toxoplasmosis, microscopy of the lesions demonstrate periaqueductal and periventricular vasculitis with necrosis.
• Fetal tissue and placenta can demonstrate t.gondii cysts with the Wright-Giemsa stain and also with immunoperoxidase staining using t.gondii–specific antibodies.

References

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