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Fig. 5.7 Electron micrograph of two intracellular T. gondii that are each beginning the second round of division by endodyogeny, as shown by the formation of daughter apical complexes (D) within each parent. Several apical organelles, including dense granules (dg), micronemes (mn) and rhoptries (rh), are seen within the parents. The parasitophorous vacuole space is filled with the tubulovesicular network (tvn), which is thought to function in parasite salvage of host metabolites. A host mitochondrion (mt) is seen at the edge of the parasitophorous vacuole. The host lysosomal compartments (ly) are labeled by graular thorium dioxide, showing that none of these bodies fuse with the parasitophorous vacuole. Magnification x 10000
(Yap and Sher, 1999a,b), neither does the longterm immunity induced by vaccination rely on nitric oxide, although it is IFN-dependent (Khan, Matsuura and Kasper, 1998). Dendritic cells may be important in the immune response to reexposure to T. gondii. Lymphocytes from donors with evidence of previous toxoplasmosis induced rapid and strong production of interleukin 12 (IL-12) from human dendritic cells, which would be expected to produce a rapid burst of IFNy (Seguin and Kasper, 1999).
The effective and balanced immune response of immunocompetent individuals controls the infection, in most cases causing little organ damage, but does not eradicate the infection. The bradyzoite cysts elicit little immune reaction and may persist for the life of the host. Changes
in the host’s immune functions may allow reactivation of actively replicating tachyzoites which must be controlled by further cell-mediated mechanisms. If the host is incapable of mounting or regulating this response, the outcome is extensive organ damage.
The primary route of infection is oral, with progression of the infection through the gastrointestinal tract to local lymphatics and spread to other organs documented in the mouse, but all of these steps have not been shown in humans (Channon and Kasper, 1996; Fadul et al., 1995;
PRINCIPLES AND PRACTICE OF CLINICAL PARASITOLOGY
Fig. 5.8 Toxoplasmic encephalitis. An area of necrosis with perivascular inflammatory infiltrate and clusters of intracellular tachyzoites (arrow). Extracellular tachyzoites are more difficult to distinguish from fragments of necrotic cells. Haematoxylin and eosin stain. Bar=50 pm
Frenkel, 1973, 1988). In mice fed bradyzoites, the first step appears to be local invasion of the small intestinal epithelium. The bradyzoite and tachy-zoite are both capable of active invasion of many cell types, and replicate within a parasite-modified vacuole (Dubremetz, 1998; Lingelbach and Joiner, 1998; Schwab et al., 1994). Bradyzoites rapidly convert to tachyzoites in vivo. In vitro the formation of bradyzoite cysts can be stimulated by various maneuvers that stress the infected cells, including change of pH or temperature or various mitochondrial poisons (Dubey et al., 1998; Dubremetz, 1998; Soete et al., 1994). The key step in spreading the infection from the localized initial site is likely infection of circulating monocytes in the lamina propria; this cell subset has been shown to be permissive for T. gondii replication in both mice and humans, and may therefore be responsible for transport of the parasite widely throughout tissues (Fadul et al., 1995).
Tachyzoites are found in all organs in acute infection, most prominently in muscle, including heart, and in liver, spleen, lymph nodes and the central nervous system (Bertoli et al., 1995; Figures 5.8, 5.9). The initial pathological lesion is necrosis caused by death of parasitized cells, with a vigorous acute inflammatory reaction. As the disease progresses, more lymphocytic infiltration develops but true granulomas are not formed. If the host controls the replication of tachyzoites effectively, tissues are restored to
Fig. 5.9 Toxoplasmic myocarditis. Intracellular tachyzoites are within a myocardial muscle cell, which is surrounded by extensive edema and inflammatory infiltrate. Geimsa stain. Bar=50 pm
anatomic integrity without scarring, and cysts containing the long-lived bradyzoites remain without sign of host reaction. The humoral immune response is rapid and may be capable of killing extracellular tachyzoites (and is of use diagnostically), but it is not protective in the mouse model (Frenkel, 1973). Control of the disease appears to depend on the elaboration of appropriate cytokines including IL-12 and IFNy (Suzuki et al., 1988a; Yap and Sher, 1999a), followed by a specific cell-mediated immunity, with CD8+ helper T cells apparently the most important subgroup (Suzuki, 1999; Yap and Sher, 1999a). In some experimental infections there is intense acute inflammation with few identifiable parasites and early death, which may be caused by an overly vigorous cytokine response to the infection (Khan et al., 1997).
CLINICAL SYNDROMES Acute Disease in Adults
Most individuals positive for T. gondii antibodies have no history of a clinical syndrome that was diagnosed as toxoplasmosis, leading to the supposition that most primary infections are asymptomatic or unrecognized. The most