Abstract
Intravenous challenge with Trypanosoma cruzi can be used to investigate the process and consequences of blood parasite clearance in experimental Chagas disease. One hour after intravenous challenge of chronically infected mice with 5×106 trypomastigotes, the liver constituted a major site of parasite accumulation, as revealed by PCR. Intact parasites and/or parasite remnants were visualized at this time point scattered in the liver parenchyma. Moreover, at this time, many of liver-cleared parasites were viable, as estimated by the frequency of positive cultures, which considerably diminished after 48 h. Following clearance, the number of infiltrating cells in the hepatic tissue notably increased: initially (at 24 h) as diffuse infiltrates affecting the whole parenchyma, and at 48 h, in the form of large focal infiltrates in both the parenchyma and perivascular spaces. Phenotypic characterization of liver-infiltrating cells 24 h after challenge revealed an increase in Mac1+, CD8+ and CD4+ cells, followed by natural killer (NK) cells. As evidence that liver-infiltrating CD4+ and CD8+ cells were activated, increased frequencies of CD69+CD8+, CD69+CD4+ and CD25+CD122+CD4+ cells were observed at 24 and 48 h after challenge, and of CD25−CD122+CD4+ cells at 48 h. The major role of CD4+ cells in liver protection was suggested by data showing a very high frequency of interferon (IFN)-γ-producing CD4+ cells 24 h after challenge. In contrast, liver CD8+ cells produced little IFN-γ, even though they showed an enhanced potential for secreting this cytokine, as revealed by in vitro T cell receptor (TCR) stimulation. Confirming the effectiveness of the liver immune response in blood parasite control during the chronic phase of infection, no live parasites were detected in this organ 7 days after challenge.
Highlights
A main feature of human and murine infections by Trypanosoma cruzi, the etiological agent of Chagas disease, is the rarity of spontaneous cure
A Latin American illness caused by the protozoan parasite Trypanosoma cruzi, has only rare spontaneous cure, and in most patients a small number of parasites persists for life in the blood and tissues, leading to chronic disorders such as cardiomyopathy
Parasite accumulation in this organ is followed by their elimination, an effect that is not immediate but seems to depend on the recruitment of leukocytes and on the local production of IFN-c, a cytokine known to increase the T. cruzi-killing capacity of phagocytes
Summary
A main feature of human and murine infections by Trypanosoma cruzi, the etiological agent of Chagas disease, is the rarity of spontaneous cure. Despite the generation of a potent anti-parasite immune response, that allows the control of parasitemia at the end of the acute phase, a small number of T. cruzi persists in the tissues. From this place, and for the lifetime of the host, the parasites occasionally gain access to the blood, where they can be detected by indirect methods such as xenodiagnosis, hemoculture, subinoculation or PCR [1,2,3]. The clearance of extracellular trypomastigotes is optimized by the coordinated cooperation of antibodies and phagocytes, a process that results in efficient parasite-destruction when phagocytes are primed by inflammatory cytokines, notably by IFNc [8]
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