Tc52 Amino-Terminal-Domain DNA Carried by Attenuated Salmonella enterica Serovar Typhimurium Induces Protection against a Trypanosoma cruzi Lethal Challenge

Abstract

In this work we immunized mice with DNA encoding full-length Tc52 or its amino-or carboxy-terminal (N-and C-term, respectively) domain carried by attenuated Salmonella as a DNA delivery system. As expected, Salmonella-mediated DNA delivery resulted in low antibody titers and a predominantly Th1 response, as shown by the ratio of IgG2a/IgG1-specific antibodies. Despite modest expression of Tc52 in trypomastigotes, the antibodies elicited by vaccination were able to mediate lysis of the trypomastigotes in the presence of complement and inhibit their invasion of mammal cells in vitro. The strongest functional activity was observed with sera from mice immunized with Salmonella carrying the N-term domain (SN-term), followed by Tc52 (STc52), and the C-term domain (SC-term). All immunized groups developed strong cellular responses, with predominant activation of Th1 cells. However, mice immunized with SN-term showed higher levels of interleukin-10 (IL-10), counterbalancing the inflammatory reaction, and also strong activation of Tc52-specific gamma interferon-positive (IFN-␥ ؉ ) CD8 ؉ T cells. In agreement with this, although all prototypes conferred protection against infection, immunization with SN-term promoted greater protection than that with SC-term for all parameters tested and slightly better protection than that with STc52, especially in the acute stage of infection. We conclude that the N-terminal domain of Tc52 is the section of the protein that confers maximal protection against infection and propose it as a promising candidate for vaccine development.

Immunization with Tc52 or its amino terminal domain adjuvanted with c-di-AMP induces Th17+Th1 specific immune responses and confers protection against Trypanosoma cruzi

“…Measurement of antigen-specific IgG and IgA was carried out by Enzyme Linked Immune Assays (ELISA) as described previously [18]. Plates were coated with recombinant Tc52 (rTc52, 2 μg/ml).…”

Vaccine-Linked Chemotherapy Improves Benznidazole Efficacy for Acute Chagas Disease

“…Limitations of this model were observed. Survival and parasite burdens in mouse models of Chagas disease give clear signals of vaccine efficacy (30,31,(57)(58)(59)(60). However, low-virulence T. cruzi infection models, in which overall survival is high, can elucidate key aspects of disease pathogenesis (61,62).…”

Coadministration of cruzipain and GM-CSF DNAs, a new immunotherapeutic vaccine againstTrypanosoma cruziinfection

“…In addition, the mucosa-associated lymphoid tissue facilitates the capture of antigen by specialized immune cells: macrophages and dendritic cells, initiating a strong humoral and cellular immune response, both locally and systemically. Thus, we recently obtained promising results in prophylactic Salmonella-based monocomponent 27,38 or multicomponent 29 vaccines against experimental infection with T. cruzi.…”