Caspase inhibition reduces lymphocyte apoptosis and improves host immune responses to <i>Trypanosoma cruzi</i> infection

Silva, Elisabeth M.; Guillermo, Landi V. C.; Ribeiro-Gomes, Flávia L.; Meis, Juliana de; Nunes, Marise P.; Senra, Juliana F. V.; Soares, Milena Botelho Pereira; DosReis, George A.; Lopes, Marcela F.

doi:10.1002/eji.200636790

Cited by 30 publications

(55 citation statements)

References 44 publications

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“…Lymphocyte apoptosis plays a deleterious role in in vivo immune responses against T. cruzi [10,39,40]. Our data showed that injection of apoptotic lymphocytes opsonized with chagasic IgG reduced parasitemia in vivo.…”

Section: Discussionmentioning

confidence: 56%

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

et al. 2010

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Phagocytic removal of apoptotic lymphocytes exacerbates replication of Trypanosoma cruzi in macrophages. We investigated the presence of Ab against apoptotic lymphocytes in T. cruzi infection and the role of these Ab in parasite replication. Both control and chagasic serum contained IgG Ab that opsonized apoptotic lymphocytes. Treatment of apoptotic lymphocytes with purified IgG from chagasic, but not control serum, reduced T. cruzi replication in macrophages. The protective effect of chagasic IgG depended on Fcc receptors, as demonstrated by the requirement for the intact Fc portion of IgG, and the effect could be abrogated by treating macrophages with an anti-CD16/CD32 Fab fragment. Chagasic IgG displayed increased reactivity against a subset of apoptotic cell Ag, as measured by flow cytometry and immunoblot analyses. Apoptotic lymphocytes treated with chagasic IgG, but not control IgG, increased production of TNF-a, while decreasing production of TGF-b1 by infected macrophages. Increased control of parasite replication required TNF-a production. Previous immunization with apoptotic cells or injection of apoptotic cells opsonized with chagasic IgG reduced parasitemia in infected mice. These results indicate that Ab raised against apoptotic cells could play a protective role in control of T. cruzi replication by macrophages.Key words: Ab . Apoptosis . Fc receptors . Phagocytosis . Trypanosoma cruzi IntroductionInfection with Trypanosoma cruzi, the causative agent of Chagas' disease, induces Ab against both parasite Ag [1-4] and self molecules [5][6][7]. Ab play a protective role in T. cruzi infection [1][2][3][4][5]7], but the mechanisms involved are not completely understood.Infection with T. cruzi induces lymphocyte apoptosis [8][9][10][11][12], and the phagocytic clearance of apoptotic lymphocytes drives replication of T. cruzi in macrophages [13]. Parasite replication results from a biochemical cascade that originates from binding of apoptotic cells Ã These authors contributed equally to this work. Eur. J. Immunol. 2010. 40: 417-425 DOI 10.1002 Immunity to infection 417 to a V b 3 integrin, followed by production of PGE 2 and TGF-b1, induction of ornithine decarboxylase and increased production of the polyamine putrescine [13]. T. cruzi is unable to synthesize putrescine and depends on uptake of exogenous putrescine for intracellular growth [14]. Phagocytosis of apoptotic cells induces production of TGF-b1, but not proinflammatory cytokines [15]. However, phagocytosis of apoptotic cells is enhanced by serum opsonins, including Ab [16], and Ab to apoptotic cells can lead to secretion of proinflammatory cytokines [15,17].Immunization with apoptotic cells induces production of autoantibodies [18]. However, it is unclear whether such autoantibodies play an immunoregulatory role. In the present study, we sought to determine whether infection with T. cruzi elicited production of Ab against apoptotic lymphocytes. We found that apoptotic lymphocytes treated with chagasic IgG induced a proinflammatory cytokine resp...

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Section: Discussionmentioning

confidence: 56%

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

et al. 2010

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“…Correlation between induction of apoptosis and growth of T. cruzi is demonstrated by the increased parasitemia elicited by injection of a modified T. cruzi recombinant protein that induces apoptosis (57). In agreement with a pathogenic role, in vivo treatment with a caspase inhibitor reduces lymphocyte apoptosis and improves protective immune responses in mice infected with T. cruzi (58). Interestingly, mice chronically infected with T. cruzi develop IgG antibodies against apoptotic cells that reduce, but do not prevent the deleterious effect of apoptotic cells on intramacrophage parasite replication (59).…”

Section: The Chronic Phase: An Equilibrium Between Parasite Killing Amentioning

confidence: 70%

Evasion of immune responses by Trypanosoma cruzi, the etiological agent of Chagas disease

DosReis

2011

Braz J Med Biol Res

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Infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects millions of people in Latin America. Infection with T. cruzi cannot be eliminated by the immune system. A better understanding of immune evasion mechanisms is required in order to develop more effective vaccines. During the acute phase, parasites replicate extensively and release immunomodulatory molecules that delay parasite-specific responses mediated by T cells. This immune evasion allows the parasite to spread in the host. In the chronic phase, parasite evasion relies on its replication strategy of hijacking the TGF-β signaling pathway involved in inflammation and tissue regeneration. In this article, the mechanisms of immune evasion described for T. cruzi are reviewed.

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“…Remarkably, infected mice treated with the general caspase inhibitor zVAD developed higher IFN- responses to parasite antigens and reduced parasitemia. (118) There are several possible explanations for the effects of caspase inhibitors attenuating the immunosuppression induced by apoptosis. First, caspase inhibitor may reduce or delay lymphocyte death.…”

Section: General Caspase Inhibition In Vivomentioning

confidence: 99%

“…(101) T cells from T. cruzi-infected mice show increased levels of active caspase-3 in vitro. (118) Treatment of cells with zVAD prior to culture abrogates the expression of active caspase-3 and both spontaneous and activation-induced cell death. Remarkably, infected mice treated with the general caspase inhibitor zVAD developed higher IFN- responses to parasite antigens and reduced parasitemia.…”

Section: General Caspase Inhibition In Vivomentioning

confidence: 99%

Targeting caspases in intracellular protozoan infections

Guillermo¹,

Pereira²,

Meis

et al. 2009

Immunopharmacology and Immunotoxicology

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Caspase inhibition reduces lymphocyte apoptosis and improves host immune responses to Trypanosoma cruzi infection

Cited by 30 publications

References 44 publications

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

Evasion of immune responses by Trypanosoma cruzi, the etiological agent of Chagas disease

Targeting caspases in intracellular protozoan infections

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