The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View

Abstract

Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver's participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.

Keywords: Chagas disease; Trypanosoma cruzi infection; hepatic immune response; liver.

Figure 1

The Trypanosoma cruzi biological cycle. When the invertebrate host feeds on a human being, or any other vertebrate host, the trypomastigote metacyclic form (1) is transmitted. Then, this form (2) rapidly invades a host cell and differentiates in the cytoplasm into amastigote forms (3), which duplicate by binary divisions. Then, these forms intracellularly differentiate into trypomastigote forms that are released (4) to infect other host cells or be obtained (5) by the invertebrate host. The trypomastigote forms then start the differentiation into epimastigote forms (6) that adhere to the insect’s intestinal epithelium. These forms also proliferate by binary divisions until their differentiation into metacyclic trypomastigote forms, reinitiating the cycle. The epimastigote and trypomastigote forms were adapted from [3]. The lower segment in blue represents the invertebrate cycle, while the upper segment represents the vertebrate hosts’ cycle. The parasite forms are not presented to scale.

Figure 2

Liver microenvironment and resident cells under steady-state conditions. The portal vein delivers blood rich in molecules from the intestinal flora to the liver. This blood flows through the hepatic liver sinusoids lined by fenestrated liver sinusoidal endothelial cells (LSEC). The normal liver contains LSECs, hepatocytes, hepatic stellate cells (HSCs), hepatic dendritic cells (HDCs), lymphocytes, and Kupffer cells (KCs). Between the sinusoid walls and hepatocyte cords, there is the Disse space. The general characteristics of each cellular population are indicated in the boxes. HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; PD-L1, programmed death-ligand 1; PRR, pattern recognition receptors; PGE2, prostaglandin E2.

Figure 3

Proposed pathways for hepatic tolerance to portal antigens and the reversion to a “pro-inflammatory” milieu after activated peripheral T lymphocyte transfer. The left panel represents the group of mice that received a parasite extract by gavage, showing CTLA-4⁺ intrahepatic T lymphocytes interacting with hepatic B7-bearing antigen presenting cells plus antigen (a). There is also IDO-1 upregulation (b), and Treg cells increase in the liver (c). We observed high levels of IL-10 and TGF-β (d), reduced numbers of effector and/or effector memory (T_em) T cells (e), and more Treg cells (f). Moreover, there was increased expression of B7-H1 in the liver stroma (g), a known down regulator of T lymphocytes’ function. The right panel represents the group that received parasite extract by gavage plus activated peripheral T lymphocytes by adoptive transfer. In this scenario, CTLA-4⁻ activated peripheral T lymphocytes would interact with APCs in the liver through the classical engagement of CD28/B7 and TCR/MHC plus peptide (h), and in this group, we observed an increased production of the pro-inflammatory cytokines IFN-γ, TNF, CCL2, and IL-6 (i). In this ambience, cells such as CTLA-4⁺ IHL, NKT, Treg, and γδ T lymphocytes (j) were reduced in the hepatic stroma, and CD4⁺ and CD8⁺ effector/T_em lymphocytes (k) were increased. In the presence of activated peripheral T cells, there is a balance between pro- and “anti-inflammatory” pathways, with increased expression of PD-1 and B7-H1 in the liver (l). Finally, there is an increase in F4/80⁺ cells in the liver (m), with still unknown functions. Adapted from [46].