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Trans-Sialidase Recombinant Protein Mixed with CpG Motif-Containing Oligodeoxynucleotide Induces Protective Mucosal and Systemic Trypanosoma cruzi Immunity Involving CD8⁺ CTL and B Cell-Mediated Cross-Priming¹

Daniel F. Hoft^2,*, Christopher S. Eickhoff^*, Olivia K. Giddings^*, José R. C. Vasconcelos^* and Maurício M. Rodrigues

^* Department of Internal Medicine and Department of Molecular Microbiology, Saint Louis University Health Sciences Center, Saint Louis, MO 63110; and Centro Interdisciplinar de Terapia Gênica (CINTERGEN) and Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (R01 AI040196 to D.F.H.), Fundação de Amparo à Pesquisa do Estado de São Paulo, and The Millennium Institute for Vaccine Development and Technology (CNPq-420067/2005-1 to M.M.R.).

² Address correspondence and reprint requests to Dr. Daniel F. Hoft, Division of Immunobiology, Departments of Internal Medicine and Molecular Microbiology, Saint Louis University Health Sciences Center, 1100 South Grand Boulevard, DRC, 8th Floor, Saint Louis, MO 63104. E-mail address: hoftdf{at}slu.edu

³ Abbreviations used in this paper: IMT, T. cruzi insect-derived metacyclic trypomastigotes; BFT, T. cruzi blood form trypomastigotes; CpG ODN, oligodeoxynucleotides containing unmethylated 5' to 3' cytosine to guanine sequences that signal through TLR-9; rTS, recombinant trans-sialidase; TS, T. cruzi trans-sialidase protein antigen; TSIR BFT, T. cruzi BFT recovered from mice after in vivo exposure to TS-specific immunity.

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