title: Cytosolic delivery of viral nucleoprotein by listeriolysin O-liposome induces enhanced specific cytotoxic T lymphocyte response and protective immunity.
abstract: Cytotoxic T lymphocytes (CTLs) are capable of conferring protection against intracellular pathogens and tumor. Protective antiviral immunity, mediated by the activation of antigenic epitope-specific CTL, can be achieved by delivering exogenous antigen into the cytosol of antigen-presenting cells. Cytosolic introduction of vaccine antigen, however, requires a specialized delivery strategy due to the membrane barrier limiting the access of macromolecules to the cytosol. In this study, we have investigated the potential ability of listeriolysin O-containing liposomes (LLO-liposomes) to deliver lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP), harnessing the intracellular invasion mechanism of Listeria monocytogenes, to stimulate a NP-specific CTL response. We have analyzed the ability of LLO-liposomes to induce an enhanced CTL response and determined the extent of CTL-mediated protection using an in vivo infection model. Mice immunized with LLO-liposomes containing NP generated a higher frequency of NP-specific CD8+ T cells with greater effector activity than the control groups immunized with either non-LLO-liposomal NP or LLO-liposomes containing control protein. Moreover, LLO-liposomal NP-immunized mice were completely protected against a lethal intracerebral challenge with a virulent strain of LCMV and were capable of clearing a chronic LCMV infection. Our study demonstrates that LLO-liposomes can be used as an efficient vaccine delivery system carrying a viral antigenic protein to generate protective antiviral immunity.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Manas
authors.initials: M
authors.lastname: Mandal
authors.forename: Kim S
authors.initials: KS
authors.lastname: Kawamura
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Kyung-Dall
authors.initials: KD
authors.lastname: Lee
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004337:Drug Carriers; D005260:Female; D006360:Heat-Shock Proteins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006460:Hemolysin Proteins; D007109:Immunity; D008081:Liposomes; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000517:prevention & control; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009698:Nucleoproteins / Q000493:pharmacokinetics*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology / Q000493:pharmacokinetics*
chemical_list: D001427:Bacterial Toxins; D004337:Drug Carriers; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D008081:Liposomes; D009698:Nucleoproteins; D014764:Viral Proteins; C038705:hlyA protein, Listeria monocytogenes