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Listeriolysin O-Deficient Listeria monocytogenes as a Vaccine Delivery Vehicle: Antigen-Specific CD8 T Cell Priming and Protective Immunity¹

Department of Microbiology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242

Strains of Listeria monocytogenes (LM) that are deficient in the virulence factor listeriolysin O (LLO) are highly attenuated and are thought not to elicit protective immunity. This failure has been attributed to the inability of the bacterium to enter the host cell cytosol and access MHC class I Ag processing machinery. We reexamined this issue using recombinant strains of LM that are deficient in LLO but express an additional CD8 T cell epitope derived from lymphocytic choriomeningitis virus. After infection with LLO-deficient strains, we find sizable priming of epitope-specific CD8 T cells and the development of a functional memory cell population. Mice primed with the LLO-deficient LM strain are equally resistant against high-dose challenge with virulent LM as mice primed with wild-type virulent bacteria and also resist heterologous challenge with lymphocytic choriomeningitis virus. Interestingly, priming with a low dose of LLO-deficient LM, which occurred in environment of reduced inflammation (IFN-), allowed rapid amplification of Ag-specific CD8 T cells by booster immunization, despite an undetectable primary response. We conclude that the generation of protective immunity by LLO-deficient strains of LM does in fact occur and that this highly attenuated LM strain may be a useful platform for vaccine delivery.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R0IAI42767, R0IAI46653, and R0IAI50073 (to J.T.H.), T32AI07511 (to S.E.H.), and American Cancer Society Grant Seed Grant IRG-77-004-28 (to V.P.B.).

² S.E.H. and V.P.B. contributed equally to this work.

³ Current address: Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Center for Immunology, Minneapolis, MN 55454.

⁴ Address correspondence and reprint requests to Dr. John T. Harty, Department of Microbiology, University of Iowa, 3-501 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242. E-mail address: john-harty{at}uiowa.edu

⁵ Abbreviations used in this paper: LM, Listeria monocytogenes; LCMV, lymphocytic choriomeningitis virus; s, secreted; ns, nonsecreted; WT, wild type; LOD, limit of detection.