Abstract
The Trypanosoma cruzi trans-sialidase (TS) is a unique enzyme with neuraminidase and sialic acid transfer activities important for parasite infectivity. The T. cruzi genome contains a large family of TS homologous genes, and it has been suggested that TS homologues provide a mechanism of immune escape important for chronic infection. We have investigated whether the consensus TS enzymatic domain could induce immunity protective against acute and chronic, as well as mucosal and systemic, T. cruzi infection. We have shown that: 1) TS-specific immunity can protect against acute T. cruzi infection; 2) effective TS-specific immunity is maintained during chronic T. cruzi infection despite the expression of numerous related TS superfamily genes encoding altered peptide ligands that in theory could promote immune tolerization; and 3) the practical intranasal delivery of recombinant TS protein combined with a ssDNA oligodeoxynucleotide (ODN) adjuvant containing unmethylated CpG motifs can induce both mucosal and systemic protective immunity. We have further demonstrated that the intranasal delivery of soluble TS recombinant Ag combined with CpG ODN induces both TS-specific CD4(+) and CD8(+) T cells associated with vaccine-induced protective immunity. In addition, optimal protection induced by intranasal TS Ag combined with CpG ODN requires B cells, which, after treatment with CpG ODN, have the ability to induce TS-specific CD8(+) T cell cross-priming. Our results support the development of TS vaccines for human use, suggest surrogate markers for use in future human vaccine trials, and mechanistically identify B cells as important APC targets for vaccines designed to induce CD8(+) CTL responses.
Highlights
The Trypanosoma cruzi trans-sialidase (TS) is a unique enzyme with neuraminidase and sialic acid transfer activities important for parasite infectivity
In the current work we have further investigated the potential of TS vaccines to protect against both acute and chronic T. cruzi infection, developed a practical strategy for TS vaccination capable of inducing both mucosal and systemic protection, and investigated mechanisms of protection induced by this TS vaccination strategy
To further explore the possibility that TS-specific immunity could be involved in an immune escape mechanism during chronic T. cruzi infection, we have studied TS-specific immunity in mice chronically infected and repeatedly challenged with Tulahuen strain T. cruzi trypomastigotes
Summary
The Trypanosoma cruzi trans-sialidase (TS) is a unique enzyme with neuraminidase and sialic acid transfer activities important for parasite infectivity. Recent studies have demonstrated that human chagasic disease correlates with levels of parasites present in cardiac tissue [3,4,5] and that chagasic disease progression can be significantly reduced by specific chemotherapy that, it may not be curative, effectively reduces parasite burden (6 – 8) These latter results strongly indicate that disease progression is predominantly caused by parasite-specific immunopathology, supporting the rationale for the development of both prophylactic and immunotherapeutic vaccines. Type 1 and type 2/3 responses have reciprocal inhibitory activities, presenting a significant obstacle for the development of vaccines designed to induce differential T cell responses in mucosal and systemic immune compartments [15,16,17,18,19] It is of critical importance for the field of vaccine immunobiology to define the specific mucosal and systemic responses that are protective against mucosally invasive intracellular pathogens and to learn how to induce the appropriate responses in mucosal and systemic tissues by vaccination. Vaccines designed to protect against Chagas disease should induce a global type 1 immune response
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