Anti-viral protection conferred by recombinant adenylate cyclase toxins from Bordetella pertussis carrying a CD8+ T cell epitope from lymphocytic choriomeningitis virus.
The elucidation of the mechanisms of antigen presentation by major histocompatibility complex class I molecules has stimulated the search for nonreplicative vectors that could deliver CD8+ T cell epitopes to the cytosol of antigen-presenting cells to trigger the activation of specific cytotoxic T lymphocytes (CTLs) in vivo. In the present study, we investigated the potential ability of an invasive adenylate cyclase toxin from Bordetella pertussis, carrying a CD8+ T cell epitope from the nucleoprotein of lymphocytic choriomeningitis virus (LCMV), to stimulate protective anti-viral immunity. Mice immunized with this recombinant toxin developed strong CTL responses against LCMV-infected target cells. Moreover, these mice were protected against an intracerebral challenge with a virulent strain of LCMV that killed all nonimmunized mice within 7 days. This protection was abolished after in vivo elimination of CD8+ T cells. A mutant toxin devoid of adenylate cyclase activity (i.e., cAMP synthesizing activity) was constructed by insertion of a dipeptide into the catalytic site of the molecule. This genetically detoxified invasive toxin carrying the LCMV epitope stimulated a strong CTL response against both peptide-coated and virus-infected target cells, and mice immunized with this molecule were fully protected against a lethal intracerebral LCMV challenge. To our knowledge, this study represents the first demonstration that a genetically detoxified bacterial toxin carrying a viral CTL epitope can stimulate efficient protective immunity.
Saron
M F
MF
Unité d'Histopathologie-Virologie Expérimentale, Institut Pasteur, Paris, France.
Fayolle
C
C
Sebo
P
P
Ladant
D
D
Ullmann
A
A
Leclerc
C
C
D000262:Adenylyl Cyclases / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D001886:Bordetella pertussis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000939:Epitopes; D011993:Recombinant Fusion Proteins; D000262:Adenylyl Cyclases