Cytosolic delivery of viral nucleoprotein by listeriolysin O-liposome induces enhanced specific cytotoxic T lymphocyte response and protective immunity

被引:22
作者
Mandal, Manas [1 ]
Kawamura, Kim S. [2 ,3 ]
Wherry, E. John [2 ,3 ]
Ahmed, Rafi [2 ,3 ]
Lee, Kyung-Dall [1 ]
机构
[1] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA
[2] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA
[3] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA
关键词
viral antigen delivery; antiviral immunity; listeriolysin O; liposomes; CTL response; CTL frequency; LCMV infection; protection;
D O I
10.1021/mp034021m
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 INIP-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.
引用
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页码:2 / 8
页数:7
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