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-priming.
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.
Hoft
Daniel F
DF
Department of Internal Medicine, Saint Louis University Health Sciences Center, Saint Louis, MO 63110, USA. hoftdf@slu.edu
Eickhoff
Christopher S
CS
Giddings
Olivia K
OK
Vasconcelos
José R C
JR
Rodrigues
Maurício M
MM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000938:Antigen-Presenting Cells / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D002908:Chronic Disease; D018503:Genome, Protozoan / Q000276:immunology; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000494:pharmacology; D016052:Protozoan Vaccines / Q000276:immunology* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D014349:Trypanosoma cruzi / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity
D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; C408982:CPG-oligonucleotide; D006023:Glycoproteins; D009838:Oligodeoxyribonucleotides; D016052:Protozoan Vaccines; D011994:Recombinant Proteins; C069715:trans-sialidase; D009439:Neuraminidase