Heterologous chimeric construct comprising a modified bacterial superantigen and a cruzipain domain confers protection against Trypanosoma cruzi infection

ANTONOGLOU MB; SANCHEZ ALBERTI ANDRES; DANIELA REDOLFI; AUGUSTO E. BIVONA; FERNANDEZ LYNCH MJ; NOLI TRUANT S; SARRATEA MB; LAURA IANNANTUONO; MALCHIODI E; MARISA FERNDANDEZ

Frontiers in immunology

Frontiers Media SA

Año: 2020

1664-3224

Chagas disease is an endemic chronic parasitosis in Latin America affecting morethan 7 million people. Around 100 million people are currently at risk of acquiringthe infection; however, no effective vaccine has been developed yet. Trypanosomacruzi is the etiological agent of this parasitosis and as an intracellular protozoan it canreside within different tissues, mainly muscle cells, evading host immunity and allowingprogression toward the chronic stage of the disease. Considering this intracellularparasitism triggers strong cellular immunity that, besides being necessary to limitinfection, is not sufficient to eradicate the parasite from tissues, a differential immuneresponse is required and new strategies for vaccines against Chagas disease need tobe explored. In this work, we designed, cloned and expressed a chimeric molecule,named NCz-SEGN24A, comprising a parasite antigen, the N-terminal domain of themajor cysteine protease of T. cruzi, cruzipain (Nt-Cz), and a non-toxic form of thestaphylococcal superantigen (SAg) G, SEG, with the residue Asn24 mutated to Ala(N24A). The mutant SAg SEGN24A, retains its ability to trigger classical activation ofmacrophages 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 withCpG-ODN, or the recombinant proteins Nt-Cz plus SEGN24A with the same adjuvant.Vaccinated mice significantly produced Nt-Cz-specific IgG titers after immunization anddeveloped higher IgG2a than IgG1 titers. Specific cell-mediated immunity was assessedby in-vivo DTH and significant responses were obtained. To assess protection, micewere challenged with trypomastigotes of T. cruzi. Both schemes reduced the parasite load throughout the acute phase, but only mice immunized with NCz-SEGN24A showedsignificant differences against control; moreover, these mice maintained 100% survival.These results encourage testing mutated superantigens fused to specific antigens asimmune modulators against pathogens.m