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Figure 3 The life cycle of T. cruzi. (1) Metacyclic trypomastigotes are released in feces of the insect and enter the vertebrate host through the bite wound. (2) Trypomastigotes invade mammalian cells (see Figure 4). (3) After 30-120 min trypomastigotes escape from the vacuole and transform into replicative amastigotes. (4) Amastigotes multiply in the cytoplasm. (5) After a number of cycles amastigotes differentiate into trypomastigotes, which will rupture the host cell. (6) Amastigotes may also lyse infected cells before differentiation into trypomastigotes, and are thereby released into circulation, invade macrophages, survive, divide and further differentiate into trypomastigotes. (7) With a blood meal, the insect vector ingests bloodstream trypomastigotes, which in the insect midgut differentiate into noninfective and replicating epimastigotes. Epimastigotes further differentiate into metacyclic trypomastigotes in the hindgut of the vector, completing the life cycle.

Figure 3 The life cycle of T. cruzi. (1) Metacyclic trypomastigotes are released in feces of the insect and enter the vertebrate host through the bite wound. (2) Trypomastigotes invade mammalian cells (see Figure 4). (3) After 30-120 min trypomastigotes escape from the vacuole and transform into replicative amastigotes. (4) Amastigotes multiply in the cytoplasm. (5) After a number of cycles amastigotes differentiate into trypomastigotes, which will rupture the host cell. (6) Amastigotes may also lyse infected cells before differentiation into trypomastigotes, and are thereby released into circulation, invade macrophages, survive, divide and further differentiate into trypomastigotes. (7) With a blood meal, the insect vector ingests bloodstream trypomastigotes, which in the insect midgut differentiate into noninfective and replicating epimastigotes. Epimastigotes further differentiate into metacyclic trypomastigotes in the hindgut of the vector, completing the life cycle.

Figure 4 T. cruzi invasion into a mammalian cell. (1) T. cruzi trypomastigotes attach to the cell surface. (2) Host cell lyso-somes (o) migrate to the attachment site. (3) Lysosomes fuse with the plasma membrane at the attachment site and start to form an intracellular vacuole around the parasite. (4) The intracellular vacuole is formed. (5) Lysosomal glycoproteins are desi-alylated by the T. cruzi trans-sialidase and sialic acid (black dots) is transferred to parasite acceptors. T. cruzi Tc-TOX (■) anchors in the lysosome membrane. (6) The vacuolar membrane is disrupted. The parasite escape into the cytoplasm, where they will differentiate into amastigotes.

Figure 4 T. cruzi invasion into a mammalian cell. (1) T. cruzi trypomastigotes attach to the cell surface. (2) Host cell lyso-somes (o) migrate to the attachment site. (3) Lysosomes fuse with the plasma membrane at the attachment site and start to form an intracellular vacuole around the parasite. (4) The intracellular vacuole is formed. (5) Lysosomal glycoproteins are desi-alylated by the T. cruzi trans-sialidase and sialic acid (black dots) is transferred to parasite acceptors. T. cruzi Tc-TOX (■) anchors in the lysosome membrane. (6) The vacuolar membrane is disrupted. The parasite escape into the cytoplasm, where they will differentiate into amastigotes.

a stage of general dysregulation. In summary, the relevance of both polyclonal activation and immuno-depression in the biology of the infection and outcome of disease is unknown. It is believed that the immunomodulation events occurring in the acute phase influence alterations later during the infection by modifying the quality of the specific immune responses.

Protective immune responses The immune response controls the high parasite load in the acute phase to produce virtually undectable parasitemia in the chronic phase. However, sterile immunity and complete parasite clearance and cure are unknown in humans and in experimental models of infection. Rather than achieving a cure, the immune response maintains a host-parasite balance which lasts for the lifetime of the infected individual.

NK cells, macrophages, B cells and both CD4+ and CD8+ T cells play important roles in resistance of mice infected with T. cruzi. Such diversity of cellular populations is reflected in manifold humoral and cellular immune effector mechanisms of destruction of both intracellular amastigotes and bloodstream trypomastigotes. Antibodies can lyse the parasite through activation of the classical or alternative pathways of complement. Antibodies might also lyse trypomastigotes through antibody-dependent cell-mediated cytotoxocity. Eosinophils, neutrophils, mononuclear cells and platelets have been shown to lyse the trypomastigotes when coated with specific antibodies. T cells can regulate production of such antibodies, lyse infected target cells or release cytokines (Table 1) that modulate different trypanocidal mechanisms of phagocytes. Whether they influence the physiology of infection in nonphagocytic cells is not known. Macrophage activation by tumor necrosis factor a (TNFa) IL-3, IFNa, IFN0, IFN-y or granulocyte-macrophage colony-stimulating factor (GM-CSF) leads to inhibition of the replication or killing of the intracellular forms of T. cruzi. Of these cytokines, IFNy has been most closely associated with host resistance. Conversely, cytokines such as IL-4, IL-10 and TGF(3 counteract the effects of IFNy during T. cruzi infection in vitro and in vivo. However, T. cruzi infection appears not to be a model for Th1/Th2 dichotomy, as in infection with Leisbmania major. Cytokines belonging to both T,, 1 and TH2 are simultaneously produced during infection in a variety of mice, but the balance between cytokines belonging to either pattern appears to influence the outcome of infection. Such cytokine balance regulates the transcriptional rate and mRNA stability of inducible nitric oxide synthase (iNOS) by macrophages, mediating high output of NO. Macrophages produce reactive oxygen species (ROS) and NO and show induction of iNOS during the course of T. cruzi infection in vivo. Both NO and ROS are toxic for the parasite in vitro, and some trypanocidal drugs, such as nifurtimox or crystal violet, act by generating such species. In addition, the superoxide anion and

Table 1 Role of cytokines in the outcome of infection with T.

cruzi in vivo and in vitro

Cytokine Effect on T. cruzi infection

IFN-y Reduces parasitemia and mortality. Activates trypanocidal activity of macrophages, mainly through induction of inducible NO synthase. The peak of production coincides with the high parasite load during the acute phase of infection

TNFtx Inhibits intracellular multiplication. Synergizes with and mediates IFN-y trypanocidal activity. It has been shown both to aggravate and protect in vivo. Produced by macrophages after in vitro infection with parasites TGFfS Inhibits IFN-y-mediated trypanocidal activation of macrophages. Is involved in parasite penetration and intracellular multiplication. Increases susceptibility to infection in vivo IL-1 Released by infected macrophages and endothelial cells. Probably associated with microcirculatory alterations, and thereby heart dysfunction

IL-2 Spontaneously released early after infection, its production is markedly suppressed during the acute phase of infection IL-3 Activates a trypanostatic activity of macrophages

IL-4 Inhibits IFN-y-mediated macrophage activation and NO release. Its levels are increased in the chronic phase of infection, especially in susceptible hosts. Increases susceptibility to infection with at least some T. cruzi strains IL-6 Decreases cumulative mortality in vivo. Released by endothelial cells after in vitro infection with T. cruzi

IL-10 Inhibits IFN-y-mediated macrophage activation.

Increases susceptibility to infection. Increased in susceptible as compared with resistant strains of mammalian hosts IL-12 Reduces parasitemia and mortality, through

IFN-y- and possibly TNFa-mediated mechanism of resistance

NO might react with each other to form peroxynitr-ite, a stronger trypanocidal molecule than its precursors. Whereas the relevance of ROS is still controversial, NO is necessary for control of the parasite load both in in vitro activated macrophages and during in vivo infection with T. cruzi.

Pathogenesis and immunopathology Different mechanisms have been proposed to participate in the pathogenesis of chagasic cardiopathy, and probably all have some degree of involvement in such a process. Microvascular changes, as manifested by platelet aggregates, increased levels of P-selectin, thrombus formation and histochemical evidence of myocardial hypoxia in humans and experimental models, might cause focal necrosis. Conversely, the reduction of parasympathetic ganglion cells in the heart and gut of chronic Chagas' patients has prompted suggestions for a role for denervation in pathogenesis. Vagal and myenteric plexus denervation could induce an increased sympathetic tone that may have a direct effect in heart arrythmogen-esis or gut megasyndrome. There is by now convincing evidence that immune responses are involved in pathogenesis. Chronic inflammatory reactions depend on a persistent antigenic stimulation by parasite antigens. Although a chronically infected host displays undectable parasitemia and very rarely tissue amastigotes, parasite antigens have been detected in inflammatory infiltrates and such lesions correlate with the severity of the disease. Autoantibodies or autoreactive cellular responses generated through polyclonal activation or by parasite antigens cross-react with mammalian neurons, lymphoid cells, laminin, ribosomal proteins, sarcolemma, myocardial p receptors and myosin. The levels of some of these antibodies correlate with the clinical status (myosin for example), and some antibodies mediate physiologic alterations in the target cells. For example, parasite cross-reactive antibodies trigger neurotransmitter-receptor interactions in myocytes and thereby alter the physiology of normal myocardium. Tissue destruction by inflammatory cells is probably facilitated by the presence of parasite antigens and ectopic expression of adhesion molecules and histocompatibility antigens on the surface of infected or noninfected cells during infection. CD8* T cells have been shown to dominate the inflammatory infiltrate; however, the pathogenic role for CDS'" T cells is not clear. In contrast, CD4+ cells from chronically infected mice comprise only 5-10% of the inflammatory infiltrate but have been shown to play a role in pathogenesis, as they are involved in the rejection of grafted syngeneic heart tissue. Hypo-thetically, almost every immunologic mechanism described as participating in protection might also be involved in tissue pathology. Whatever the damaging mechanism, no data presented as yet can explain the prolonged latent period between the initial infection and the pathologic changes 5—40 years later in human infection.

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