Toxoplasma gondii

Morphology

• The actively multiplying asexual form in the human host is an obligate, intracellular, parasite, pyriform in shape and approximately 3-6 µ

• This parasite called tachyzoite, has a cell membrane, nucleus, and various organelles

• A collection of tachyzoites can fillup a host cell, develop a parasite membrane around themselves and become a cyst

• In the encysted stage the organism, called a bradyzoite, becomes metabolically quiescent but remains viable

• There is evidence that tachyzoites are antigenically distinguishable from bradyzoites

• The cysts contain 50 to several thousand bradyzoites and measure from 10-100 µ in diameter

• Within the intestinal epithelial cell of the cat, a variety of morphologic forms has been described, ultimately leading to male and female gametocytes

• The fertilized macrogametes develop into nearly spherical oocysts that rupture out of intestinal epithelial cells

• When passed in cats’ feces, the oocysts measure 10-13 µ in diameter

• The oocysts wall has two layers and contain undifferentiated material, but the content develop into two sporocyst within several days after being passed

• Each sporocyst, in turn, contain 4 sporozoites

Life Cycle

• T.gondii tachyzoites multiply within host cells by a specialized form of division called endodyogeny, in which two daughter cells are formed within a mother cell

• As the distended host cells fill up with parasites, they rupture, releasing parasite that enter new cells

• The infected host cell may swell up develop a membrane, and become a cyst

• The tachyzoites consume oxygen, use dextrose and preformed as well as precursor of pyrimidines and evolved CO2 but cannot synthesize purines, their respiration is cyanide- sensitive

• Toxoplasma can grow in any mammalian or avian organs or tissues, developing in the brain, eye and skeletal muscles

• In the natural cycle, mice and rats containing infective cysts are eaten by the cat, which serve as definitive host for the sexual stage of the parasite

• The cyst wall is digested, releasing organisms (bradyzoites) that penetrate epithelial cells of the small intestine

• Several generations of intracellular multiplication occur, finally culminating in development of micro- and macrogametes

• Fertilization of the latter results in development of oocysts that are discharged into the intestinal lumen by rupture of infected intestinal epithelial cells

• After eating cysts, cats excrete toxoplasma oocysts as early as 4 days later; these increase and then taper off by 14 days

• Oocysts require 1-5 days, depending upon aeration and temperature, after passage to sporulate

• Ingestion of the sporulated oocyst initiates infection by sporozoites in the intermediate host, which can be virtually any animal

• The oocyst-induced infection also begins in the intestinal epithelium, but the tachyzoites multiply and spread to more distant organs to form cysts that are again infective when ingested by susceptible animal

• Thus, although the domestic cat or some wild species of Felidae can produce the the oocyst, a wild variety of animals, including sheep, cattle, and pigs can become infected by ingestion of the oocyst

• These infected animals will, in turn, harbor infected cysts within muscle tissue

• Organism within the cysts remain viable for years

Hence, human infections can result:– 1. from eating raw or partially cooked beef, fork or

mutton containing toxoplasma cyst– 2. by ingestion of material with infected cat feces

Epidemiology

• Toxoplasmosis is cosmopolitan, antibody survey indicate that from 25-75% various populations are chronically but asymptomatically infected

• In areas where cats are numerous, sanitation is poor, and the climate is humid and mild, favoring long-term oocyst viability, the presence of antibodies to Toxoplasma is high in children

• The other mode of transmission, via ingestion of partially cooked or raw meat, is probably more common in developed urban areas

• Although infection is common disease is rare• The congenital infection is required by

transplacental transmission from mothers who develop toxoplasmosis during pregnancy, not from mothers who have already been infected before pregnancy

Pathology and Symptomatology

• Ordinarily, T.gondii is relatively benign, well-adapted parasite, and its disease-producing properties have been attributed to virulent strains, or the site of the parasite

Congenital Toxoplasmosis

• This occurs is in about 1-5% per 1000 pregnancies

• Unlike in adults, it is often severe and even fatal, varying in degree of severity with the age of the fetus at infection and the antibody protection from the mother

• The child may present the typical syndrome of intracerebral calcifictiona, chorioretinitis, hydrocephally, microcephaly, psychomotor disturbances, and convulsion

• Visceral and muscular lesions are also present• Occasionally the infection is milder, and there

maybe complete recovery

• Spinal fluid findings are variable • In severe overt cases there are xantochromia,

increased cells and protein, and occasionally even the organisms

• Milder cases show only slight increases in cells and protein

• It is estimated that of the congenital infetions, 5-15% of the babies will die

• 8-10% will have severe brain and eye damage

• 10-13% will have moderate to severe visual handicaps

• 58-72% will be asymptomatic at birth, with a small proportion developing active retinochoroiditis or mental retardation as children or young adult

• Since transplacental transmission takes place during initial exposure to the parasite, second congenital infections rarely, if ever, occur

• The chorioretinal lesions in infants are severe, extensive and bilateral

• There is an intense edema of the retina and various degrees of degeneration and necrotic inflammation, with perivascular and general cellular infiltration

• There may be an optic neuritis• Milder forms of congenital infection are seen

as ocular involvement in older children and young adult

• This is manifested only as a retinochoroiditis of varying severity, but without other evidence of generalized disease

• The exact cause of toxoplasmic retinochoroiditis of this late-onset type is not known

• It may be due to localized proliferation of organism or an immunologic hypesensitivity reaction

Acquired or Reactivity Toxoplasmosis

• After infection and regional lymph node invasion, the parasite is blood-borne to many organs where intracellular multiplication takes place

• Parasitemia persist for several weeks, and with the production of antibody, cysts form in various tissues

• The patients are asymptomatic

• There are 2 main clinical types of acquired postnatal toxoplasmosis:– 1. the more common, mild lymphatic form,

resembling infectious mononucleosis, is characterized by cervical and axillary lymphadenophaty, malaise, muscle pain and irregular low fever. Slight aemia, low blood pressure, leukopenia, lymphocytosis, and slightly altered liver function maybe present

– 2. the other type is characterized by acute, fulminating, disseminated infections, often with skin rash, high fever, chills, and prostration. Meningoencephalitis, hepatitis, pneumonitis, and myocarditis may be present

• Toxoplasmosis has long been known to occur as an opportunistic infection because of immunosuppression associated with organ transplantation and treatment of certain neoplastic disease

• In 1980s, toxoplasmic encephalitis as a complication of AIDS has emerged as one of the most common parasitic disease in AIDS patients

• CNS involvement by toxoplasma may even appear as the first clinical manifestation of AIDS

• Early symptoms can be headache, fever, lethargy, and altered mental status, with progression to focal neurologic deficits and convulsions

• By CT scans or MRI imaging, single or multiple lesion with predilection for basal ganglia and junction of gray and white matter can be visualized

• Even in the presence of extensive brain lesions the parasite remains confined to the CNS and does not spread to other organs

• This syndrome represents reactivation of a latent infection, so virtually all patients will have demonstrable IgG antibodies to Toxoplasma from a acquired previously infection

• Changes in antibody levels are unpredictable and IgM responses do not occur, so the usual serial antibody determinations are not helpful in diagnosis of toxoplasmosis complicating AIDS

• The ocular involvement that occurs in later life following an inapparent congenital infection is probably a reactivationtoxoplasmosis also, although the exact mechanism is unknown

• It should be emphasized, however, tha there are other causes of retinochoroiditis and uveitis, probably most of it not a result of toxoplasma infection

• Serologic tests are very important in the diagnosis of toxoplasmosis

• Because of the common occurence of antibodies to the parasite in the general population, diagnosis by serologic means requires demonstration of a significant increase in antibody titers

• A very high antibodi level is not sufficient evidence in itself for a diagnosis of active toxoplasmosis, although it may be a useful clue for further diagnostic measures

• Congenital infections may be difficult to diagnose serologically because maternal IgG crosses the placental barrier and will appear and persist for several months in the circulation of the newborn

• But since IgM antibodies do not cross the placenta, demonstration of antitoxoplasma IgM at birth or up to several months of age is presumptive evidence of conenital toxoplasmosis

• If tests that measure only IgG are available, it is necessary to show that antibodies persist or increase in titer during the first 6 months or so of life as evidence of congenital infection

• For measurement of IgM antibodies, the double-sandwhich ELISA test is the most specific and sensitive

• The indirect fluorescent antibody (IFA) test is also used for both IgM and IgG determinations

• Other serologic test tests for IgG antibody include the ELISA and IHA

• The Sabin-Feldman dye test that was first develop requires preparation and use of living Toxoplasma organisms, so it is rarely used now

• A complement-fixation (CF) test which can identify recent infections because of a slow rise and rapid fall in CF antibody, is not used because it is difficult to standardize and is technically demanding

• A delayed-type skin test has been described in toxoplasmosis, but antigens are not commercially available, and the significance of the test for diagnostic purposes is nor clear

• If tissue of fluid suspected of containing parasites is available, a supension of the material should be inoculated into mice or cell cultures

• Laboratory mice are very susceptible to infection, and specimens of biopsied lymph nodes, muscle, spinal fluid, or blood have often been positive, especially in acute cases

• A positive result in mice can be shown either by actual isolation of the organism or by their development of antibody

• One problem in interpretation of a positive isolation from tissue, especially muscle tissue, is that the orgasnisms recovered may represent encysted parasites from a previous infection

• Detection of parasite DNA by polymerase chain reaction (PCR) is being evaluated as a diagnostic measure

Treatment

• Symptomatic infections should be treated with pyrimethamine

• The adult dosage is 25-50 mg per day orallyfor 3-4 weeks, plus 2-6 g daily trisulfapyrimidines orally for the same period

• The two drugs act synergistically to inhibit nucleic acid synthesis of microorganisms

• The sulfa by preventing incorporation of paraaminobenzoic acid in the synthesis of folate

• Pyrimethamine by inhibiting dihydrofolate reductase (DHFR), a later stage in the process

• Mild lymphatic toxoplasmosis will often subside without requiring treatment

• It is often difficult to decide wether ocular toxoplasmosis, without systemic involvement, should be treated

• If the retinochoroiditis is considered to be an active process, most opthalmologists treat with both corticosteroids and combined sulfa and pyrimethamine as outlined above

• AIDS patients are much more susceptible to sulfa allergies and bone marrow supression by pyrimethamine

• If severe toxicity requires stopping sulfa therapy, it may still be possible to manage by restarting with smaller but slowly increasing doses after dexamethasone pretreatment

• Folinic acid at 10 mg per day will prevent or reversethe bone marrow suppresionof pyrimethamine without inhibiting its action because parasite can not utilize exogenous folate

• Pregnant women should not be treated with pyrimethamine

• In this situation, one alternative drug is spiramycin

• Another drug that might be used in emergency situations is clindamycin

• Atovaquone, a hydroxynaphthoquinone, appears to be one of the more promising new drugs for treatment of toxoplasmic encephalitis in AIDS