Ocular Toxoplasmosis

Robert B. Nussenblatt

Key concepts

•Ocular disease can occur after both congenital and acquired disease.

•Recurrent disease frequently is seen as a satellite lesion.

•Immunodeficient patients are at risk for acquired disease and possibly reactivation of old disease.

Toxoplasmosis is a common disease in both mammals and birds. The disease is caused by the obligate intracellular protozoan Toxoplasma gondii. It is thought that this organism infects at least 500 million persons worldwide, and at least 50% of the adult population in the United States has the chronic symptomless form of the disease.1 A survey of ophthalmologists in the US reported that 55% of those who responded saw one or more active ocular toxoplasmosis cases in last 2 years, and that 93% of those who responded had seen inactive cases in the last 2 years.2 In the United Kingdom the estimated lifetime risk for ocular toxoplasmosis has been calculated to be 18 in 100 000.3 In the developing world, its prevalence is probably underestimated.

A prospective study in Sierra Leone identified toxoplasmosis as the most common cause of uveitis. In Nepal, over 50% of those coming to hospital, not only for uveitis, but for other disorders such as malignancies and obstetric problems, had antibodies to toxoplasma, with over 5% being IgM positive, indicative of a recent infection.4 The disease can cause a passing flu-like condition that has little consequence, but it can also cause lymphadenopathy, serious and sometimes fatal disease in immunocompromised hosts, spontaneous abortions, and congenital disease. For the ophthalmologist it is one of the most frequently encountered posterior uveitides, classically producing a necrotic retinitis. It is also one of the few uveitides for which we can potentially make a definitive diagnosis. In the past few years our understanding of the organism and its interrelationship with its host has brought into question several concepts that had been readily accepted in ophthalmology practice.

Organism

In 1908 T. gondii was first found in the brain of the North African rodent the gondi, by Nicolle and Manceaux5 and then by Splendore6 in a rabbit in Brazil. Janku7 first des­ cribed postmortem findings in a child who had died of

disseminated toxoplasmosis. He noted what were probably Toxoplasma organisms in the eye, but inoculation of animals with infected tissue did not induce disease. The transmission of the organism to animals via inoculation of infected human tissue was accomplished by Wolf and coworkers.8 Helenor Campbell Wilder identified the presence of the organism in the eye in 1952, confirming that it was the cause of uveitis.9

T. gondii is a ‘cosmopolitan’ parasite, being found all over the world. Members of the cat family are the definitive hosts. Oocysts of Toxoplasma are 10–12 m in length and oval in shape. They are found uniquely in the intestinal mucosa of cats. Once they are released, they can be spread to humans or to other animals through a variety of vectors. Although invariably thought to be ingested, the organism may also enter the host through other mucosal surfaces.10 Humans can also be infected secondarily by ingesting meat (pork and lamb particularly, as well as chicken in endemic areas, but probably not beef) contaminated with Toxoplasma cysts. The two forms of the organism that can be found in humans are cysts and tachyzoites (Fig. 14-1). The cysts are up to 200 m in diameter, contain hundreds to thousands of organisms, and have a propensity for cardiac tissue, muscle, and neural tissue, including the retina. The cyst structure is complex and can include elements from the host. Cysts can remain intact outside of a host in soil for at least 1 year. Not all the factors that cause ultimate rupture of the cyst and the release of tachyzoites are totally clear. The tachyzoite is oval or arc shaped and about 6–7 mm in length. It is an obligate intracellular organism that actively proliferates and is the cause of the acute disease. The organism’s entry into and residence within the host cell are clearly complex and dynamic events, and much is still not known. Joiner11 found that the organism forms a parasitophorous vacuole that surrounds the parasite and that lacks plasma membrane markers from the host. It will not fuse with other compartments in the cell, and is sheltered from all cellular traffic.

Many of the antigens of the organism have been identified (Table 14-1 and Fig. 14-2). Perhaps the most studied is SAG 1 or p30. This major surface antigen has a molecular mass between 27 and 30 kDa. It is useful in the serologic diagnosis of infection12 and may play a role in the parasite’s ability to invade a cell.13 In animal models, immunization with this antigen or adoptive transfer of immune cells recognizing this antigen will confer a degree of protection against active infection. The p30 gene sequence has been deduced14 and its mRNA appears to be 1500 nucleotides in length.

A second antigen that has been characterized is SAG 2 or p22. This cell surface antigen (molecular mass 22 kDa) can

A

B

Figure 14-1.  A, Tachyzoites in culture stained with immunofluorescent dye. B, Toxoplasma cysts containing large numbers of tachyzoites. (Courtesy of Leon Jacobs, MD.)

Table 14-1  Toxoplasma gondii antigens

Organism

SAG1, p30, 1E11 Diagnosis of infection antibody-dependent cell-mediated cytotoxicity, 3–5% of protein in certain strains

F3G3

Figure 14-2.  Cartoon showing anatomic areas from which purified

Toxoplasma antigens have been isolated.

participate in antibody-dependent, complement-mediated lysis of the tachyzoite.15 It appears to be part of a complex phagosomal reticular network.16 A third antigen that has been studied is known as the F3G3 antigen. This 58-kDa antigen is cytoplasmic and not expressed on the cell surface. Passive transfer of antibody that reacts to this antigen has been successful in protecting animals from a lethal challenge by the Toxoplasma organism.17 The study of excreted/secreted antigens of toxoplasmosis continues18 because it has been demonstrated that 90% of the circulating antigens detected during active infection are those that are actively excreted.19 These antigens could be used as a basis for vaccine development, in that immunization against these antigens might abrogate rapid entry of the tachyzoite into the cell. Of interest have been attempts to classify the specific clonal lineages that may cause human toxoplasmosis. Howe and Sibley20 determined the population genetic structure of T. gondii by using multiple restriction fragment length polymorphism analysis. They studied six loci in 106 independent Toxoplasma isolates from humans and animals. Although not separate strains, three distinct lineages seemed to be found, with only four of the isolates showing an extensively mixed genotype. In this study human isolates were found in all three lineages, although the majority of those had a type III genotype. However, one study performed in Europe reported that the cases evaluated were of the type I genotype.21 This was also the type reported from Brazil.22 However, the story is most probably more complicated than that. Grigg and colleagues23 reported an abundance of atypical strains (i.e., lineages) that were associated with toxoplasmic disease. In the 12 samples they evaluated, three had typical type I lineage whereas five of 12 had recombinant genotypes typical of two lineages. Howe and colleagues24 genotyped 68 of 72 samples isolated from human disease using the p22 (SAG2) antigen. They found that the vast majority of these 68 isolates (81%) were classified as type II, whereas only 10% were type I and 9% were type III. Khan et al.25 evaluated

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