Toxoplasma Gondii

J. P. Dubey

General Concepts

Clinical Manifestations

Infection is often asymptomatic. Immunocompetent individuals may present with fever, lymphadenopathy, muscle aches, and headache. Congenitally infected children may suffer impaired vision and mental retardation. Immunosuppressed patients may have central nervous system disease (encephalitis).

Structure and Life Cycle

Members of the cat family (Felidae) are the definitive hosts; many mammals and birds serve as intermediate hosts. Infection is contracted by ingesting either oocysts or meat containing live organisms. Organisms enter the intestinal epithelium and can spread to many host tissues. Individual organisms are lunate, about 6 X 2 m, and multiply within host cells. Tissue cysts containing hundreds of quiescent organisms may form as infection wanes. Toxoplasma reproduces sexually only in cats. Organisms infecting the intestinal epithelium produce oocysts which are shed in the feces. Mature oocysts are approximately 12 m in diameter and contain eight infective sporozoites.

Classification and Antigenic Types

Toxoplasma gondii, a member of the Apicomplexa, is the sole species.

Multiplication and Life Cycle

A sexual multiplication by cell division can occur in virtually any host cell.


Host cells are destroyed by active multiplication of T gondii. Necrotic foci may result. Congenital infection often involves the retina and brain; focal chorioretinitis may result in impaired vision. Brain involvement in immunosuppressed patients may lead to large necrotic abscesses. Disease reactivation in immunosuppressed patients may result from the rupture of a tissue cyst.

Host Defenses

Immunocompetent individuals mount an effective cell mediated immune response that eradicates active infection within weeks or months and results in immunity against reinfection. Tissue cysts are unreactive and may persist for the life of the host.


Toxoplasmosis shows a nonseasonal worldwide distribution. Most natural infections are acquired by ingesting undercooked meat containing tissue cysts or food contaminated by cat feces.


Diagnosis is based on serology and on histologic examination of tissues.


Infection may be prevented by thorough cooking of meat and by proper management of cats. Acute cases are treated with sulfadiazine and pyrimethamine.


Toxoplasma gondii is an intestinal coccidium that parasitizes members of the cat family as definitive hosts and has a wide range of intermediate hosts. Infection is common in many warm-blooded animals, including humans. In most cases infection is asymptomatic, but devastating disease can occur.

Clinical Manifestations

Toxoplasma gondii usually parasitizes both definitive and intermediate hosts without producing clinical signs. In humans, severe disease is usually observed only in congenitally infected children and in immunosuppressed individuals, including patients with acquired immune deficiency syndrome (AIDS). Postnatally acquired infections may be local or generalized and are rarely severe in immunocompetent individuals. Lymphadenitis is the most common manifestation in humans. Any node can be infected, but the deep cervical nodes are the most commonly involved. Infected nodes are tender and discrete but not painful; the infection resolves spontaneously in weeks or months. Lymphadenopathy may be accompanied by fever, malaise, fatigue, muscle pains, sore throat, and headache.

Encephalitis is an important and severe manifestation of toxoplasmosis in immunosuppressed patients including patients with AIDS. Symptoms may include headache, disorientation, drowsiness, hemiparesis, reflex changes, and convulsions. Coma and death may ensue.

Prenatally acquired T gondii often infects the brain and retina and can cause a wide spectrum of clinical disease. Mild disease may consist of slightly diminished vision, whereas severely diseased children may exhibit a classic tetrad of signs: retinochoroiditis, hydrocephalus, convulsions, and intracerebral calcifications. Hydrocephalus is the least common but most dramatic lesion of congenital toxoplasmosis (Fig. 1). Ocular disease is the most common sequela.

FIGURE 84-1 Girl with hydrocephalus due to congenital toxoplasmosis. (From Dubey JP, and Beattie CP. Toxoplasmosis of animals and Man. CRC Press, Baca Raton, Florida, 52, 1988.)

Toxoplasma gondii is capable of causing severe disease in animals other than humans. It is one of the major causes of abortion in sheep and goats in many countries, including Australia and the United States. It is important to diagnose toxoplasmic abortion to distinguish it from other causes of abortion, because congenital transmission of T gondii occurs only during the initial infection of the mother and the animal is safe for breeding thereafter. Cats, dogs, and many other pets can die of pneumonia, hepatitis, and encephalitis due to toxoplasmosis. In dogs, clinical toxoplasmosis is often associated with concurrent distemper virus infection. Certain species of marsupials and New World monkeys are highly susceptible to toxoplasmosis.

Structure, Multiplication, and Life Cycle

The life cycle of T gondii was described only in 1970, when it was discovered that the definitive hosts are members of the family Felidae, including domestic cats. Various warm-blooded animals serve as intermediate hosts. Toxoplasma gondii is transmitted by three known modes: congenitally, through the consumption of uncooked infected meat, and via fecal matter. Figure 2 shows the life cycle of T gondii.

Figure 84-2 Life cycle of Toxoplasma gondii. Cats, the definitive hosts of T gondii, can become infected by ingesting sporulated oocysts or (most often) infected animals. The oocysts are infectious to most mammals and birds. Toxoplasma can be transmitted to intermediate hosts through oocysts, by carnivorism, or transplacentally. Transplacental transmission is most important in humans and sheep. (From Dubey JP, Toxoplasmosis. J Am Vet Med Assoc 189:166, 1986.)

Cats acquire Toxoplasma by ingesting any of three infectious stages of the organism: the rapidly multiplying forms called tachyzoites (Fig. 3), the quiescent bradyzoites that occupy cysts in infected tissue (Fig. 4), and the oocysts shed in feces (Fig. 5). Successful infection of the cat is revealed by the shedding of oocysts in the feces. The chance of infection and the prepatent period (the time between infection and the shedding of oocysts) varies with the stage of T gondii ingested. Fewer than 50 percent of cats shed oocysts after ingesting tachyzoites or oocysts, whereas nearly all cats shed oocysts after ingesting tissue cysts. Only the cyst-induced cycle has been studied in detail.

FIGURE 84-3 Tachyzoites of T gondii.

A. Extracellular (arrow) released from host cells. Compare their size with red blood cells and a lymphocyte. Impression smear, Giemsa stain. Bar = 20 m.

B. Intracellular in cell culture. Note a group arranged in a rosette (arrow) and vacuole (arrowhead) around a tachyzoite. Immunohistochemical stain with a tachyzoite-specific monoclonal antibody. Bar = 20 m.

C. Transmission electron micrograph of an intracellular tachyzoite. Note a parasitophorous vacuole (PV) around the tachyzoite. Parasite organelles visible in this picture include a conoid (c), micronemes (m), dense granules (dg) nucleus (n) and rhoptries (r). Bar=0.8 m. (Courtesy of Dr. D.S. Lindsay, Auburn University, AL.)

FIGURE 84-4 Tissue cysts of T gondii.

A. Tissue cyst freed from mouse brain. Note a thin (arrow) cyst wall enclosing hundreds of bradyzoites. Unstrained. Bar = 20 m.

B. Two tissue cysts (arrows) in section of brain. Hematoxylin and eosin stain. Bar = 20 m.

C. Transmission electron micrograph of a small tissue cyst in cell culture. Note thin cyst wall (arrow) enclosing 6 bradyzoites (arrowheads). Bar = 1.0 m. (Courtesy of Dr. D.S. Lindsay, Auburn University, Auburn, AL.)

When a cat ingests meat containing tissue cysts, the cyst wall is dissolved by the proteolytic enzymes in the stomach and small intestine, releasing the bradyzoites. The bradyzoites, which are a slow multiplying stage, penetrate the epithelial cells of the small intestine and initiate the formation of numerous asexual generations before the sexual cycle (gametogony, the production of gametes) begins (Fig. 5A). After the male gamete (Fig. 5B) fertilizes the female gamete, two walls are laid down around the fertilized zygote to form the oocyst, which is excreted in the feces in an unsporulated stage (Fig. 5C).

FIGURE 84-5 Sexual states of T gondii

A. Schizonts (double arrowheads), female gamonts (arrows), and male gamonts (arrowheads) in section of superficial epithelial cells of the small intestine of a cats. Hematoxylin and eosin stain. Bar = 15 m.

B. Three male gametes each with 2 flagella (arrowheads) compared with a merozoite (arrow). Impression of intestinal epithelium of a cat. Giemsa stain. Bar = 10 m.

C. Unsporulated oocytes (arrowheads) in feces of a cat. Note 2 oocysts of another feline coccidium, Isospora felis (arrowheads). Isospora felis sporulates faster than T gondii. The oocysts on top of the picture already contains 2 sporocysts while all T gondii oocysts are unsporulated. Unstained. Bar - 65 m.

D. Transmission electron micrograph of a sporulated oocyst. Note thin oocyst wall (arrow), 2 sporocysts (arrowheads) and 4 sporozoites (double arrowheads) in sporocysts. Bar - 2.25 m. (Courtesy of Dr. D.S. Lindsay, Auburn University, Auburn, AL.)

Oocysts measure approximately 10 by 12 m. Sporulation occurs outside the body, and the oocyst becomes infectious 1 to 5 days after excretion. Each sporulated oocyst contains two sporocysts and each sporocyst contains four sporozoites (Fig. 5D). Sporulated oocysts are remarkably resistant and can survive in soil for several months.

At the same time that some bradyzoites enter the surface epithelial cells of the feline intestine and multiply there to produce oocysts, other bradyzoites penetrate the lamina propria and begin to multiply as tachyzoites. Tachyzoites are about 6 X 2 m in size and generally lunate (Fig. 3A). Within a few hours of infection, tachyzoites may disseminate to extraintestinal tissues through the lymph and blood. Tachyzoites can enter almost any type of host cell (Fig. 3C) and multiply until the host cell is filled with parasites and dies (Fig. 3B). The released tachyzoites enter new host cells and multiply. This cycle may result in microfoci of tissue necrosis. The host usually overcomes this phase of infection, and the parasite then enters the "resting" stage in which bradyzoites are isolated in tissue cysts. Tissue cysts are formed most commonly in the brain, liver, and muscles. Cysts in neural tissues are up to 60 m in diameter and contain hundreds of bradyzoites in a thin membrane (Fig. 4). Tissue cysts usually cause no host reaction and may remain for the life of the host.

In nonfeline intermediate hosts, such as humans or mice, the extraintestinal cycle of T gondii is similar to the cycle in cats. However, sexual stages are produced only in the feline definitive hosts.


Most cases of toxoplasmosis in humans are probably acquired by the ingestion of either tissue cysts in infected meat or oocysts in food contaminated with cat feces. Bradyzoites from the tissue cysts or sporozoites released from oocysts penetrate the intestinal epithelial cells and multiply in the intestine. Toxoplasma gondii may spread both locally to mesenteric lymph nodes and to distant organs by invading the lymphatics and blood. Necrosis in intestinal and mesenteric lymph nodes may occur before other organs become severely damaged. Focal areas of necrosis may develop in many organs. The clinical picture is determined by the extent of injury to these organs, especially to vital and vulnerable organs such as the eye, heart, and adrenals. Toxoplasma gondii does not produce a toxin; necrosis is caused by intracellular multiplication of tachyzoites.

Opportunistic toxoplasmosis in AIDS patients usually represents reactivation of chronic infection. The predominant lesion of toxoplasmosis - encephalitis in these patients is necrosis, which often results in multiple abscesses, some as large as a tennis ball (Fig. 6).

FIGURE 84-6 Section of brain from an AIDS patient with fatal toxoplasmosis. Note a large focus of necrosis, 2 tissue cysts (arrows) and numerous tachyzoites (arrowheads - all black dots are tachyzoites). Immunohistochemical stain with anti-T gondii serum Bar - 100 m.

Host Defenses

The host may die from toxoplasmosis but much more often recovers and acquires immunity. Inflammation usually follows necrosis. By about the third week after infection, Toxoplasma gondii tachyzoites begin to disappear from visceral tissues and may localize as tissue cysts in neural and muscular tissues. Toxoplasma tachyzoites may persist longer in the spinal cord and brain because immune responses are less effective in these organs. Chronic infections may be reactivated locally (for example, in the eye). Reactivation possibly results from the rupture of a tissue cyst. Probably tissue cysts rupture periodically during the life of the host, and the bradyzoites released are normally destroyed by the host's immune responses. This reaction may cause local necrosis accompanied by inflammation. Hypersensitivity is said to play a major role in such reactions; however, in immunocompetent hosts the infection usually subsides, with no local renewed multiplication of Toxoplasma. In immunosuppressed patients, rupture of a tissue cyst may result in renewed multiplication of bradyzoites into tachyzoites, and the host may die from toxoplasmosis. The cause of cyst rupture is not known. Chronic latent T gondii infection can be experimentally reactivated by excessive doses of corticosteroids, antilymphocyte serum and other immunosuppressive therapies.


Toxoplasma gondii infection in humans is widespread throughout the world. Approximately half a billion humans have antibodies to T gondii. The incidence of infection in humans and animals may vary in different parts of a country. The cause for these variations is not yet known: environmental conditions, cultural habits, and animal species are among factors that may determine the degree of natural spread of Toxoplasma gondii. Only a small proportion (less than 0.1 percent) of people acquire infection congenitally. Immunocompetent mothers of congenitally infected children do not give birth to infected children in subsequent pregnancies. However, repeated congenital infection can occur in mice, rats, guinea pigs, and hamsters without reinfection from outside sources.

The relative frequency with which postnatal toxoplasmosis is acquired by eating raw meat and by ingesting food contaminated by oocysts from cat feces is unknown and difficult to investigate. Both modes of infection are reported to cause clinical toxoplasmosis. Toxoplasma gondii infection occurs commonly in many animals used for food (for example, sheep, goats, pigs, and rabbits). Infection is less prevalent in cattle than in sheep or pigs.

Oocysts are shed by cats - not only the domestic cat - but also other felids such as ocelots, margays, jaguarundi, bobcats, Pallas cats, and Bengal tigers. However, oocyst formation is greatest in the domestic cat. Widespread natural infection is possible because a cat may excrete millions of oocysts after ingesting few tissue cysts. Oocysts are resistant to most ordinary environmental conditions and can survive in moist conditions for months and even years. Invertebrates such as flies, cockroaches, and earthworms can spread oocysts mechanically.

Only a few cats may be involved at any one time in spreading T gondii in an area: at any given time as little as 1 percent of the domestic cat population in the United States is shedding oocysts. It is not known whether cats shed oocysts only once or several times in nature. Under experimental conditions, cats usually do not shed oocysts after reinoculation with T gondii tissue cysts, but this immunity to T gondii in cats does wane with time.


Diagnosis of toxoplasmosis can be aided by serologic or histocytologic examination. Clinical signs of toxoplasmosis are nonspecific and cannot be depended on for a definite diagnosis; toxoplasmosis clinically mimics several other infectious diseases.

Many serologic tests have been used to detect antibodies to T gondii. The most reliable of these is the Sabin-Feldman dye test. Live virulent tachyzoites of T gondii are used as antigen and are exposed to dilutions of the test serum and to a complement accessory factor resembling complement that is obtained from Toxoplasma-antibody free-human serum. This test is sensitive and so far is the most specific test for toxoplasmosis. Its main disadvantages are its high cost and the human hazard of using live organisms.

The indirect fluorescent antibody test (IFAT) overcomes some of the disadvantages of the dye test. In IFAT, killed tachyzoites of Toxoplasma, which are available commercially, are used as antigen. Titers obtained by IFAT are similar to those from the dye test. Disadvantages of the IFAT are that a microscope with UV light is needed, fluorescent anti-species globulin is required for each species to be tested, and false-positive titers may occur in hosts with anti-nuclear antibodies. The suitability of IFAT in animal diagnostic work is therefore limited, but it has proved useful in diagnosing acquired human toxoplasmosis. Other serologic tests including the indirect hemagglutination test, the latex agglutination test, modified agglutination test, and the enzyme-linked immunoabsorbent assay (ELISA), offer some advantages. For example, agglutination tests are easy to perform.

Soluble antigens used for indirect hemagglutination tests are now commercially available in several countries, including the United States. Although this test is easy to perform, it usually does not detect antibodies during the acute phase of toxoplasmosis. In the modified agglutination test, whole killed tachyzoites are used as antigen, and the test serum is treated with 2-mercaptoethanol to eliminate nonspecific agglutinins. The ELISA test using soluble antigens appears to be specific and may become the standard test in the future.

A single positive serum sample proves only that the host has been infected at some time in the past. Serologic evidence for an acute acquired infection is obtained when antibody titers rise by a factor of 4 to 16 in serum taken 2 to 4 weeks after the initial serum collection, or when specific IgM antibody is detected. The finding of antibody in even undiluted serum is useful in the diagnosis of ocular toxoplasmosis because patients with this disorder usually have low T gondii antibody titers.

Diagnosis can be made by finding T gondii in host tissue removed by biopsy or at necropsy. This procedure is particularly useful in immunosuppressed patients or patients with AIDS, in whom antibody synthesis may be delayed and low. Toxoplasma gondii infection can be rapidly diagnosed by making impression smears of lesions on glass slides. After drying for 10 to 30 minutes, the smears are fixed in methyl alcohol and stained with Giemsa stain. Well-preserved T gondii organisms are crescent-shaped and stain well with any of the Romanowsky stains (Fig. 3A); however, degenerating organisms common in lesions usually appear oval and have cytoplasm that stains poorly compared to the nucleus. A diagnosis of toxoplasmosis should not be made unless organisms with the typical structure are seen, as degenerating host cells may resemble degenerating T gondii parasites. In thin sections the tachyzoites are oval to round and usually do not stain differently from host cells. Tissue cysts are occasionally encountered in areas with lesions (Fig. 4B). Tissue cysts are usually spherical and have silver-positive walls; the bradyzoites stain strongly with periodic acidSchiff stain. Immunohistochemical staining and polymerase chain reaction (PCR) can be used to identify T gondii tissue cysts or tachyzoites in tissues, even those fixed in formalin. Electron-micrographic examination can aid in diagnosis (Fig. 3C). Computed tomography techniques are also useful in the diagnosis of human cerebral toxoplasmosis. Inoculation of biopsy materials into laboratory mice and/or cell cultures can help diagnosis.


Sulfonamides and pyrimethamine (Daraprim) are two drugs widely used to treat toxoplasmosis in humans. They act synergistically by blocking the metabolic pathway involving p-aminobenzoic acid and the folic-folinic acid cycle, respectively. These two drugs usually are well tolerated by the patient, but sometimes thrombocytopenia, leukopenia, or both may develop. These effects can be overcome without interrupting treatment by administering folinic acid and yeast because the vertebrate host can utilize presynthesized folinic acid, whereas T gondii cannot. The commonly used sulfonamides, sulfadiazine, sulfamethazine, and sulfamerazine, are all effective against toxoplasmosis. Generally, any sulfonamide that diffuses across the host cell membrane is useful in antitoxoplasmid therapy. Although these drugs are helpful when given in the acute stage of the disease, usually they will not eradicate infection when active multiplication of the parasite occurs. Because sulfa compounds are excreted within a few hours of administration, they must be administered in daily divided doses. Spiramycin, a drug used in France to treat pregnant women to minimize the effects of congenital toxoplasmosis, is not approved for toxoplasmosis in the United States. As yet, there are no effective drugs to kill tissue cysts.

No killed vaccine is currently available to reduce or prevent congenital infections in humans and animals, but research to develop such an agent is under way. A live vaccine using a nonpersistent T gondii strain is available in Europe and New Zealand to reduce abortion in sheep.

To prevent T gondii infection, several precautions should be taken. Meat should be cooked to 66C throughout before eating. Hands should be washed with soap and water after handling meat. Raw meat should never be fed to cats; only dry or canned food or cooked meat should be fed. Cats should be kept indoors and litter boxes changed daily. Cat feces should be flushed down the toilet or burned. Litter pans should be cleaned by immersing them in boiling water. Gloves should be used while working in the garden. Children's sandboxes should be covered when not in use.


Dubey JP, Beattie CP: Toxoplasmosis of Animals and Man. CRC Press, Boca Raton, FL, 1988

Gazzinelli RT, Denkers EY, Sher A.: Host resistance to Toxoplasma gondii: model for studying the selective induction of cell-mediated immunity by intracellular parasites. Infect Agent Dis 2:139, 1993

Georgie VA: Management of toxoplasmosis. Drugs, 48:179, 1994

Guerina NG, Hsu HW, Meissner HC, Meissner HC, et al. Neonatal serologic screening and early treatment for congenital Toxoplasma gondii infection. N Eng J Med, 330:1858, 1994

Remington, JS, McLeond R, Desmonts G.: Toxoplasmosis. In: Remington JS, Klein JO, (eds.): Infectious Diseases of the Fetus and Newborn Infant. Philadelphia: W.B. Saunders Company, 1995