Abstract
Chagas disease is an endemic chronic parasitosis in Latin America affecting more than 7 million people. Around 100 million people are currently at risk of acquiring the infection; however, no effective vaccine has been developed yet. Trypanosoma cruzi is the etiological agent of this parasitosis and as an intracellular protozoan it can reside within different tissues, mainly muscle cells, evading host immunity and allowing progression towards the chronic stage of the disease. Considering this intracellular parasitism triggers strong cellular immunity that, besides being necessary to limit infection, is not sufficient to eradicate the parasite from tissues, a differential immune response is required and new strategies for vaccines against Chagas disease need to be explored. In this work, we designed, cloned and expressed a chimeric molecule, named NCz-SEGN24A, comprising a parasite antigen, the N-terminal domain of the major cysteine protease of T. cruzi, cruzipain (Nt-Cz), and a non-toxic form of the staphylococcal superantigen (SAg) G, SEG, with the residue Asn24 mutated to Ala (N24A). The mutant SAg SEGN24A, retains its ability to trigger classical activation of macrophages without inducing T cell apoptosis. To evaluate, as a proof of concept, the immunogenicity and efficacy of the chimeric immunogen vs. its individual antigens, C3H mice were immunized intramuscularly with NCz-SEGN24A co-adjuvanted with CpG-ODN, or the recombinant proteins Nt-Cz plus SEGN24A with the same adjuvant. Vaccinated mice significantly produced Nt-Cz-specific IgG titers after immunization and developed higher IgG2a than IgG1 titers. Specific cell-mediated immunity was assessed by in-vivo DTH and significant responses were obtained. To assess protection, mice were challenged with trypomastigotes of T. cruzi. Both schemes reduced the parasite load throughout the acute phase, but only mice immunized with NCz-SEGN24A showed significant differences against control; moreover, these mice maintained 100% survival. These results encourage testing mutated superantigens fused to specific antigens as immune modulators against pathogens.
Highlights
Pathogens have evolved a diverse range of strategies to subvert the host immune system and survive
We demonstrated that the chimeric antigen, named NCz-SEGN24A adjuvanted with CpG-ODN, was able to protect against infection with T. cruzi, improving the performance of the administration of non-conjugated N-terminal domain of Cz (Nt-Cz) and SEGN24A antigens
Structural studies strongly suggested that higher affinity of staphylococcal enterotoxin G (SEG)-mVβ8.2 complex is due to the presence of five hydrogen bonds established between SEGN24 and different residues of the TCR variable β chain
Summary
Pathogens have evolved a diverse range of strategies to subvert the host immune system and survive. An important immune response is detected during this phase, it is inefficient to eradicate the parasite, allowing the development of the disease chronic period, which extends for decades. This stage is characterized by a low or undetectable parasitemia and most of the patients remain asymptomatic. With the aim to develop an effective vaccine against T. cruzi to prevent or treat the infection, many antigens have been tested in preclinical studies in combination with different adjuvants [Reviewed in Cazorla et al [7]]. In previous work from our laboratory, an engineered chimeric immunogen named Traspain was designed containing Nt-Cz as one of the key parasitic molecules, with very promising results [18, 19]
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