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.
Chagas disease, 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. In a murine model of chronic T. cruzi infection we observed that the liver plays an important role in the clearance of blood-circulating parasites. Moreover, 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-γ, a cytokine known to increase the T. cruzi-killing capacity of phagocytes. Our findings contribute to the knowledge of T. cruzi-host interaction, showing the participation of a non-lymphoid organ in parasite control. In addition, they contribute to understanding the multifaceted role the liver plays in the immune response.