The Liver Plays a Major Role in Clearance and Destruction of Blood Trypomastigotes in Trypanosoma cruzi Chronically Infected Mice

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.

Trypanosoma cruzi -Induced Activation of Functionally Distinct αβ and γδ CD4 − CD8 − T Cells in Individuals with Polar Forms of Chagas' Disease

“…It has been shown that mice infected with the parasite display a 40-to 100-fold increase in the frequency of liver ␥␦ CD4 Ϫ CD8 Ϫ lymphocytes, associated with expression of IFN-␥ (45). Interestingly, the same group later showed that the liver is an important organ for parasite clearance in chronic infection (46). An increase in the DN T-cell frequency in the liver of animals infected with Plasmodium was also associated with The frequency of ␥␦ DN T cells expressing the cytokines of interest following in vitro stimulation with T. cruzi was determined as described in Materials and Methods for each patient and then used to calculate regulatory ratios by dividing the frequency of cells producing IL-10 (a downregulatory cytokine) by the frequency of cells producing IFN-␥, TNF-␣, or IL-17.…”

Advances and challenges towards a vaccine against Chagas disease

“…30 IFNγ producing CD4 + and CD8 + T cells also play a key role in the liver for the clearance of blood trypomastigotes. 31 These cells are stimulated following oral infection, which is supposed to be a common route of infection for several animal reservoir species. 32 Thus, there is now a growing consensus that a protective immune response against T. cruzi requires the activation of a Th1 immune profile, with the stimulation of CD8 + T cells, while antibodies may play a rather secondary role.…”

Challenge of Chronically Infected Mice with Homologous Trypanosoma cruzi Parasites Enhances the Immune Response but Does Not Modify Cardiopathy: Implications for the Design of a Therapeutic Vaccine

“…Sylvio X10/4 is a low-virulence T. cruzi clone that yields no patent parasitemia in immunocompetent mice but induces low-level subpatent parasitemia that is revealed by amplification methods (19). Challenging Sylvio X10/4 chronically infected mice with a single i.v.…”

“…challenge of Y strain-infected chronic mice with homologous parasites, the liver parenchyma is infiltrated by a high number of memory CD8 ϩ cells, but very few CD8 ϩ effector cells (19). Another reason that could contribute to the absence of a consistent modification of the cardiopathy after sustained challenge is that the boosted immune response would be restricted to the blood, lungs, liver, and lymphoid organs (19); therefore, its impact upon the local inflammatory response in the heart could have been negligible. Thus, even if the levels of T. cruzi-specific IgG in the heart tissue would be similar to those observed in the serum, the same might not have occurred regarding the inflammatory cells (effector T cells, monocytes, etc.…”