The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease

Abstract

Trypanosoma cruzi interacts with the different arms of the innate and adaptive host's immune response in a very complex and flowery manner. The history of host-parasite co-evolution has provided this protozoan with means of resisting, escaping or subverting the mechanisms of immunity and establishing a chronic infection. Despite many decades of research on the subject, the infection remains incurable, and the factors that steer chronic Chagas disease from an asymptomatic state to clinical onset are still unclear. As the relationship between T. cruzi and the host immune system is intricate, so is the amount and diversity of scientific knowledge on the matter. Many of the mechanisms of immunity are fairly well understood, but unveiling the factors that lead each of these to success or failure, within the coordinated response as a whole, requires further research. The intention behind this Review is to compile the available information on the different aspects of the immune response, with an emphasis on those phenomena that have been studied and confirmed in the human host. For ease of comprehension, it has been subdivided in sections that cover the main humoral and cell-mediated components involved therein. However, we also intend to underline that these elements are not independent, but function intimately and concertedly. Here, we summarize years of investigation carried out to unravel the puzzling interplay between the host and the parasite.

Keywords: Chagas disease; Trypanosoma cruzi; adaptive immune response; cellular immunity; humoral immunity; immune evasion; innate immune response; parasite.

Figure 1

T. cruzi has mechanisms to inhibit the complement system. The parasite proteins involved in the modulation of the three complement activation pathways are indicated in black boxes. TcCRT, T. cruzi calreticulin; T-DAF, trypomastigote decay acceleration factor; TcCRP, T. cruzi complement regulatory protein; TcCRIT, T. cruzi complement C2 receptor inhibitor trispanning.

Figure 2

T. cruzi evades the microbicidal action of the macrophage by escaping from the phagolysosome into the cytoplasm, and by using enzymes that detoxify oxygen and nitrogen reactive species. The parasite enters the cell and escapes from the normal phagolysosome pathway, before its differentiation, and replication (Left). On the (Right), the peroxidases used by the parasite to inactivate different components of the oxidative burst imposed by activated macrophage are represented. TcCPX, T. cruzi cytosolic tryparedoxin peroxidases; TcMPX, T. cruzi mitochondrial tryparedoxin peroxidases; TcAPX, T. cruzi ascorbate-dependent haemoperoxidase; TcGPXI, T. cruzi glutathione peroxidases I; TcGPXII, T. cruzi glutathione peroxidases II.

Figure 3

T. cruzi modulates the functionality of dendritic cells, affecting their ability to activate mechanisms of the adaptive immune response. GIPL, T. cruzi glycosylinositolphospholipids. Blue shaded boxes represent factors and mechanisms considered beneficial for the host.

Figure 4

T. cruzi is a target of NK lymphocytes, which are one of the main cells of the innate immunity contributing to parasite clearance. However, T. cruzi also has mechanisms that modulate NK lymphocytes function. Blue shaded boxes represent factors and mechanisms considered beneficial for the host.

Figure 5

B cell-mediated response is central to the control of T. cruzi infection, but is also affected by parasite mechanisms that favor its escape and are associated with pathogenesis. The beneficial factors for the host are highlighted in blue shaded boxes, while the factors considered harmful to the host are shown in red shaded boxes. T-DAF, trypomastigote decay acceleration factor; TcTs, T. cruzi Transialidase; TcGDH, T. cruzi Glutamate dehydrogenase.

Figure 6

CD8⁺ T lymphocytes play a fundamental role in the control of parasitaemia and the elimination of cells infected with T. cruzi, but their chronic stimulation impairs their function. In addition, CD8⁺ T cells are involved in the pathogenic inflammatory processes of Chagas disease. The beneficial factors for the host are highlighted in blue shaded boxes, while the factors considered harmful to the host are shown in red shaded boxes. ASP, amastigote surface proteins; TcTs, T. cruzi transialidase; TcPRP, T. cruzi paraflagellar rod protein; KMP11, kinetoplastid membrane protein 11; TSA-1, trypomastigote surface antigen-1.

Figure 7

CD4⁺ T lymphocytes activate, enhance or modulate mechanisms of the immune response against T. cruzi infection. The control of the disease requires a balanced response in which there is a compromise between the activation of microbicidal functions and the control of inflammatory damage. The beneficial factors for the host are highlighted in blue shaded boxes, while the factors considered harmful to the host are shown in red shaded boxes. KMP11, kinetoplastid membrane protein 11; TcMUC, T. cruzi mucins.