Trypanosoma cruzi trans-Sialidase as a Potential Vaccine Target Against Chagas Disease

Abstract

Chagas' disease is caused by the protozoan Trypanosoma cruzi, described in the early 20^th century by the Brazilian physician Dr. Carlos Chagas. There was a great amount of research devoted to diagnosis, treatment and prevention of the disease. One of the most important discoveries made since then, impacting the understanding of how the parasite interacts with the host's immune system, was the description of trans-sialidase. It is an unique enzyme, capable of masking the parasite's presence from the host, while at the same time dampening the activation of CD8+ T cells, the most important components of the immune response. Since the description of Chagas' disease in 1909, extensive research has identified important events in the disease in order to understand the biochemical mechanism that modulates T. cruzi-host cell interactions and the ability of the parasite to ensure its survival. The importance of the trans-sialidase enzyme brought life to many studies for the design of diagnostic tests, drugs and vaccines. While many groups have been prolific, such efforts have encountered problems, among them: the fact that while T. cruzi have many genes that are unique to the parasite, it relies on multiple copies of them and the difficulty in providing epitopes that result in effective and robust immune responses. In this review, we aim to convey the importance of trans-sialidase as well as to provide a history, including the initial failures and the most promising successes in the chasing of a working vaccine for a disease that is endemic in many tropical countries, including Brazil.

Keywords: Chagas disease; Trypanosoma cruzi; sialic acid; trans-sialidase; vaccine.

Figure 1

Effects of Trypanosoma cruzi trans-sialidase (TS) on the host immune system. The TS enzyme can be secreted by parasite or anchored in the membrane of trypomastigote forms of T. cruzi. The active form incorporates sialic acid from host sialoglycoproteins to acceptor molecules in the parasite membrane. The inactive form has no enzymatic activity and functions as a lectin. This sialylation allows the escape of parasite from detection by the immune system, allowing its survival and the establish the infection.

Figure 2

Immune response model for trans-sialidase (TS)-based vaccines. In the immunization of mice with vaccines based on recombinant TS, exogenous antigens are usually processed and presented by antigen presenting cells (APC) via MHC class II, recognized by CD4 T cells. This pathway will stimulate B cells to produce and secrete TS-specific antibodies (Humoral response). Certain types of APC such as dendritic cells can process and present exogenous antigens via MHC class I, recognized by CD8 T cells, a process known as cross-priming. Both TS-specific CD8 and CD4 T cells can differentiate into cells with cytotoxic activity capable of killing Trypanosoma cruzi-infected cells as macrophage (Effector response). In addition, a group of specific-TS CD4 T cells (Foxp3) known as regulatory T cells are responsible for controlling the pro-inflammatory response in the host (Regulatory response). The immunization of animals with vaccines based on TS has reduced parasitemia, tissue damage and consequently the mortality rate.