Mechanisms underlying immunosuppression induced by Trypanosoma cruzi

Trypansoma cruzi affects immune responsiveness in mammalian hosts. Studies with patients and infected animals have defined some of the immunological dysfunctions but not the underlying mechanisms. Recent work using an in vitro model system of T. cruzi-human lymphocyte interactions has made it possible to uncover specific alterations in human lymphocyte activation induced by this parasite. Felipe Kierzenbaum and Marcelo Sztein discuss recent advances in our understanding of the processes that lead to impaired human lymphocyte function and that might be involved in the immunosuppression seen in the acute phase of Chagas disease.     

The innate immune response to Trypanosoma cruzi infection

Trypanosoma cruzi infection is a major public health problem in Latin America. The host innate immune system plays a pivotal role in the recognition of T. cruzi infection and the subsequent development of adaptive immunity. In this review, we focus on the TLR-dependent and -independent innate immune responses to T. cruzi.     

Trypanosoma cruzi immune evasion mediated by host cell-derived microvesicles

The innate immune system is the first mechanism of vertebrate defense against pathogen infection. In this study, we present evidence for a novel immune evasion mechanism of Trypanosoma cruzi, mediated by host cell plasma membrane-derived vesicles. We found that T. cruzi metacyclic trypomastigotes induced microvesicle release from blood cells early in infection. Upon their release, microvesicles formed a complex on the T. cruzi surface with the complement C3 convertase, leading to its stabilization and inhibition, and ultimately resulting in increased parasite survival. Furthermore, we found that TGF-β-bearing microvesicles released from monocytes and lymphocytes promoted rapid cell invasion by T. cruzi, which also contributed to parasites escaping the complement attack. In addition, in vivo infection with T. cruzi showed a rapid increase of microvesicle levels in mouse plasma, and infection with exogenous microvesicles resulted in increased T. cruzi parasitemia. Altogether, these data support a role for microvesicles contributing to T. cruzi evasion of innate immunity.     

Suppression of mouse lymphocyte responses to mitogens in vitro by Trypanosoma cruzi

Maleckar J. R. and Kierszenbaum F. 1984. Suppression of mouse lymphocyte responses to mitogens in vitro by Trypanosoma cruzi. International Journal for Parasitology14: 45–52. The ability of T. cruzi to inhibit mitogen-induced mouse lymphocyte responses was studied to find out if the organism itself is involved in the production of the immunosuppression that occurs during the acute phase of Chagas' disease. Significant suppression of normal spleen cell responses to concanavalin A (a T cell-specific mitogen) or to bacterial lipopolysaccharide (a B cell-specific mitogen) were seen when the concentration of either trypomastigote or epimastigote forms of the parasite reached or exceeded 2.5 × 10⁶ organisms/ml in the cultures. The inhibitory effect was noted over wide ranges of concentrations of either mitogen. Since spleen cells stimulated with mitogenic solutions that had been absorbed with 1 × 10⁷ parasites/ml produced significant responses, the suppressive effect could not be attributed just to mitogen removal by the parasites. Preparations of T. cruzi disrupted by freezing and thawing also inhibited mitogen-induced responses. This indicated that production of suppression was not a result of parasite competition for essential medium nutrients and that trypanosome viability was not required. Suppression was demonstrable only when the parasites were incorporated into the cultures within 12 h after mitogenic stimulation. These results taken together indicate that T. cruzi has the ability to modulate directly or indirectly lymphocyte function by interfering with the initial stages of commitment to lymphoproliferation.     

One fate of bloodstream trypomastigote forms of Trypanosoma cruzi after immune clearance: an ultrastructural study

The fate of bloodstream forms of Trypanosoma cruzi in tissues of mice was studied after immune elimination from circulation. Observations using transmission electron microscopy showed platelet thrombi occluding small vessels in the lung, liver, and spleen, and phagocytosed parasites in different stages of destruction within macrophages, neutrophils, and eosinophils. It is suggested that no particular cell population is a potential effector, but that different cells act in concert to destroy the parasites. The mechanism of this destruction might be related to intra- and extracellular mechanisms with trypanolytic activity.     

Endothelial cell signalling induced by trans-sialidase from Trypanosoma cruzi

The protozoan responsible for Chagas' disease, Trypanosoma cruzi , expresses on its surface an unusual trans -sialidase enzyme thought to play an important role in host–parasite interactions. Trans -sialidase is the product of a multigene family encoding both active and inactive proteins. We have demonstrated that despite lacking enzymatic activity due to a single mutation, Tyr342-His, inactive trans -sialidase displays sialic acid binding activity, with identical specificity to that of its active analogue. In this work we demonstrate that binding of a recombinant inactive trans -sialidase to molecules containing α2,3-linked sialic acid on endothelial cell surface triggers NF-κB activation, expression of adhesion molecules and upregulation of parasite entry into host cells. Furthermore, inactive recombinant trans -sialidase blocks endothelial cell apoptosis induced by growth factor deprivation. These results suggest that inactive members of the trans -sialidase family play a role in endothelial cell responses to T. cruzi infection.     

Trypanosoma cruzi: early resistance induced by culture-derived trypomastigotes

Previous observations in this laboratory showed that injection of culture-derived trypomastigotes (CT), in CBA/J mice, induced an early increased resistance that was detected 24-72 hr after antigen injection and permitted mice to survive a challenge of 10(5) blood trypomastigotes (BT) corresponding to 2000 LD50%. Present experiments were conducted to determine the optimal conditions for inducing this early resistance and to investigate the early morphological changes which occurred in blood and lymphoid organs of mice infected with either BT or CT. Among nine antigens tested, only living CT showed a protective effect permitting most of mice to survive 30 days after BT challenge, while control mice injected with PBS or other antigens died at 10 +/- 1 days. A dose-response relationship was seen when different doses of CT were tested, higher doses of CT inducing higher survival and lower parasitemia. Injection of CT by either an im or ip route induced similar degrees of resistance but significantly different results were obtained when mice were challenged by using ip or im routes. Higher parasitemia and lower survival were always obtained when animals were challenged by the ip route. Within 72 hr, mice injected with BT presented a lymphopenia which reached a maximum at 48 hr, a depletion of thymic cortical zone, and splenomegaly with hyperplasia of the white pulp and congestion of the red pulp. No gross alterations were observed in animals infected with CT. Overall data suggest that the early resistance is a specifically induced phenomenon and that BT and CT induce different early reactions in the CBA/J lymphoid organs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electronmicroscopic observations on lysis of Trypanosoma cruzi epimastigote by normal rabbit serum.

The lytic effects of serum from a non-immunized rabbit on epimastigotes of Trypanosome cruzi were studied by electronmicroscopy. The first detectable change was the appearance of a fuzzy deposit over the whole surface of the epimastigote. Soon after this, pellicular microtubules disappeared without change of axonemal microtubules. Circular lesions were observed by negative staining, corresponding to the lesion of antibody-mediated lysis caused by complement.     

Trypanosoma cruzi: immunosuppressed response to different antigens in the infected mouse.

Trypanosoma cruzi: Immunosuppressed response to different antigens in the infected mouse. Experimental Parasitology45, 190–199. Trypanosoma cruzi infection in mice results in functional changes in the normal immunological responses to heterologous antigens. An immunosuppression of the 19 and 7S antibody response is observed in infected animals against both a particulate antigen and against soluble antigens. Furthermore, the immune response to the soluble T-independent antigens, DNP-Ficoll and LPS, was also similarly impaired when antigen was administered to trypanosome-infected animals. The suppression of the immune response to these antigens does not seem to involve an alteration in the macrophage, as evidenced by a normal uptake and handling of soluble ¹³¹I-labeled HSA and by a normal immune response when antigen-exposed peritoneal macrophages from trypanosome-infected mice were transferred to normal mice. These data support the concept that T. cruzi induces an immunosuppression to both T-dependent and T-independent antigens and that the depression observed is not due to an alteration in macrophage function.     

Inhibition by Trypanosoma cruzi of interferon-gamma production by mitogen-stimulated mouse spleen cells

Infection by Trypanosoma cruzi is accompanied by severe immunosuppression during the acute period. As part of our studies, to define the alterations caused by Trypanosoma cruzi in lymphocyte function, we examined in this work the interferon-gamma (IFN-gamma)-producing capacity of mitogen-stimulated mouse spleen and human peripheral blood mononuclear cells in the presence or absence of blood forms of the parasite. Co-culture of phytohaemagglutinin- or concanavalin A-stimulated spleen cells from normal mice with T. cruzi significantly decreased the levels of IFN-gamma activity found in the supernatants at 48 or 72 h. In contrast, human peripheral blood mononuclear cells, though suppressed by T. cruzi in their capacity to proliferate upon mitogenic stimulation, showed no significant decrease in IFN-gamma production. The addition of exogenous IFN-gamma did not reverse the suppressive effect of T. cruzi on either mouse or human cells. These results revealed, for the first time, the ability of T. cruzi to impair IFN-gamma production by activated mouse lymphocytes. The lack of restoration by exogenous IFN-gamma suggested that the reduced levels of this lymphokine were not, at least by themselves, the causative factor of reduced lymphoproliferation.     

Trypanosoma cruzi: identification of specific epimastigote antigens by human immune sera

Soluble antigens from epimastigotes of Trypanosoma cruzi were analyzed by western blot in terms of their reactivity with sera from patients with Chagas' disease. In addition, sera from patients with visceral (AVL) and tegumental leishmaniasis (ATL) were also tested in order to identify cross-reactivities with Trypanosoma cruzi antigens. Twenty eight polypeptides with molecular weights ranging from 14 kDa to 113 kDa were identified with sera from Chagas' disease patients. An extensive cross-reactivity was observed when sera from human visceral leishmaniasis were used, while only a slight cross-reaction was observed with sera from tegumental leishmaniasis. On the other hand, 10 polypeptides specifically reacting with sera from Chagas' disease patients were identified. Among them, the antigens with molecular weights of 46 kDa and 25 kDa reacted with all sera tested and may be good candidates for specific immunodiagnosis of Chagas' disease.