Antiviral cytotoxic T-cell memory by vaccination with recombinant Listeria monocytogenes.
Listeria monocytogenes is a facultative intracellular bacterium that is able to escape phagocytic vesicles and replicate in the cytoplasm of infected cells. As with viral vectors, this intracytoplasmic life cycle provides a means for introducing foreign proteins into the major histocompatibility complex class I pathway of antigen presentation. Using recombinant L. monocytogenes (rLM) strains expressing the full-length nucleoprotein (NP) or a single cytotoxic T-lymphocyte (CTL) epitope from lymphocytic choriomeningitis virus (LCMV), we analyzed antiviral CTL responses induced by rLM vaccination. After vaccination, rLM was cleared from the host within 7 days while inducing an LCMV-specific ex vivo CD8+ effector CTL response. Virus-specific CTL memory was maintained for 6 months postvaccination, as demonstrated by vigorous secondary CTL responses after in vitro stimulation. A single immunization with rLM that expressed either the full-length NP gene or the CTL epitope alone resulted in LCMV NP-specific CTL precursor frequencies of approximately 1/10(4) CD8+ T cells. A second rLM vaccination resulted in enhanced virus-specific CTL activity and in vitro proliferation. rLM-vaccinated mice were protected against chronic viral infection by an accelerated virus-specific memory CTL response. These mice cleared infectious virus as well as viral antigen, suggesting that sterilizing immunity was achieved. In contrast to mice that received wild-type LM, rLM-vaccinated mice were protected from virally induced immunosuppression and splenic atrophy associated with chronic LCMV infection. The ability to elicit long-term cell-mediated immunity is fundamental in designing vaccines against intracellular pathogens, and these results demonstrate the efficacy of recombinant LM vaccination for inducing protective antiviral CTL memory.
Slifka
M K
MK
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Shen
H
H
Matloubian
M
M
Jensen
E R
ER
Miller
J F
JF
Ahmed
R
R
D000818:Animals; D000956:Antigens, Viral / Q000032:analysis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002522:Chlorocebus aethiops; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007156:Immunologic Memory; D007700:Kinetics; D008089:Listeria monocytogenes / Q000276:immunology* / Q000302:isolation & purification; D008099:Liver / Q000821:virology; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000517:prevention & control; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000302:isolation & purification; D051379:Mice; D008807:Mice, Inbred BALB C; D009698:Nucleoproteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014614:Vaccines, Synthetic; D014709:Vero Cells; D010948:Viral Plaque Assay; D014765:Viral Vaccines
D000956:Antigens, Viral; D015395:Histocompatibility Antigens Class I; D009698:Nucleoproteins; D010446:Peptide Fragments; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; C094246:nucleoprotein peptide 118-126, lymphocytic choriomeningitis virus