Characteristics of the organism and its antigens

Life cycle of Trypanosoma cruzi

T. cruzi, the causative agent of Chagas' disease in humans, infects 16-20 million people in Central and South America and constitutes a prominent health problem. The parasite is a kinetoplastid protozoan whose life cycle alternates between an insect belonging to the family Reduviidae, and a mammalian host. Transmission is initiated by insect vectors which after a blood meal defecate and release infective metacyclic trypomastigotes near the bite wound. These infective stages differentiate from epimastig-otes, the noninfective replicative form that live in the insect gut. Both forms are flagellated and highly motile. In contrast to the African trypanosomes, the vertebrate stages of T. cruzi are obligate intracellular pathogens and must enter host cells to replicate. After disruption of the membrane-bounded vacuole, parasites escape to the cytoplasm and differentiate into amastigotes, less motile with a very short flagel-lum and spherical body (Figure 1). After a 24 h lag period, amastigotes start dividing by binary fission, which occurs 7-10 times. After 5-7 days, more than 500 parasites have accumulated in the cytoplasm. When the replicative period is completed, amastigotes differentiate into trypomastigotes, the host cell ruptures and parasites are released into the bloodstream; thus, infection disseminates to other tissues. These released forms, equivalent to the metacyclic trypomastigotes, are called bloodstream trypomastigotes and are able to invade nearly every kind of nucleated cell (Figure 2). The T. cruzi life cycle (Figure 3) is completed when trypomastigotes are ingested by blood-sucking insect vectors. Amastigotes released from ruptured cells are also able to invade new host cells, probably involving different receptors from those used by trypomastigotes.

Invasion of the mammalian cell

Several antigens from the trypomastigote as well as host cell receptors are involved in sequential processes leading to invasion. The ability of T. cruzi to invade almost every nucleated cell from any mammalian species indicates the presence of ubiquitous and conserved receptor(s) on the host cell. Among the parasite molecules involved in binding to the host cell, a relevant role has been attributed to trypomastigote stage-specific molecules of a large family that includes trans-sialidases/sialidases. Sialic acid on the surface of host cells influences the invasion process. T. cruzi parasites do not synthesize sialic acid, but make use of transialidases that transfer mammalian sialic acid to highly glycosylated mucin-like acceptors (35-50 kDa) on the parasite surface. Treatment with antibodies to both trans-sialidase or the mucin acceptors, desialylation of parasites or treatment with tunicamycin (which blocks glycosylation) inhibit infection, and mutants defective in sialic acid are more resistant to infection. Moreover, trans-sialidase released inside the phagolysosome desialylates lysosomal proteins, allowing activity of a parasite-encoded acidic pore-forming molecule (Tc-TOX or

Figure 1 Photomicrograph of T. cruzi amastigotes in the cytoplasm of mouse peritoneal macrophages (316 x magnification).
Figure 2 Scanning electron micrograph of a T. cruzi trypo-mastigote invading a fibroblast cell (L-929) (25000 x magnification). (Courtesy of Dr L Nilsson and D Sunnemark.)

hemolysin) immunologically related to the C9 component of complement, and probably involved in escape into the cytosol. Penetrin, a 60 kDa trypomas-tigote-specific heparin-binding protein, has also been implicated in attachment to host cells. On the host surface, receptors binding fibronectin (as P,-integrins) and collagen play a role in the invasion process.

T. cruzi does not bind well to the host plasma cell membranes at 4°C, suggesting the need for energy-dependent mechanisms. In particular, those depending on parasite energy appear to play a key role in invasion. T. cruzi trypomastigotes invade the mammalian cell through a unique mechanism, distinct from phagocytosis, and without the need of pseudopodia formation and actin polymerization. Clusters of lysosomes gather in close proximity to the host plasma cell membrane at regions in contact with trypomastigotes. The parasite slides gradually into the host cell and fusion of lysosomes probably provides the membrane required for the formation of a vacuole that surrounds the parasite (Figure 4). Such an interaction is accompanied by, and probably depends on, alterations of cellular homeostatis, involving signal transduction events such as an increase in the intracellular concentration of free Ca2+ transients, both in the host cell and the infecting parasite. Ca2+ elevation in the cell is mediated by a parasite soluble factor that mediates its activity through activation of host cell phospholipase C, at least in some cellular populations. Buffering or depleting intracellular Ca2+ results in inhibition of T. cruzi entry, indicating a physiologic role for such ions in the infection. T. cruzi invasion also directly activates the transforming growth factor 3 (TGF|3) signaling pathway which is in turn required for parasite entry into the mammalian cells. Cruzipain, a cysteine protease from T. cruzi, is also thought to be involved in differentiation between amastigotes and trypomastigotes.

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