Directed antigen delivery as a vaccine strategy for an intracellular bacterial pathogen

doi:10.1073/pnas.0509381103

Directed antigen delivery as a vaccine strategy for an intracellular bacterial pathogen

*Immunology Research, Earle A. Chiles Research Institute and Veterans Affairs Medical Center, Portland, OR 97239; and
^†Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115

Edited by John J. Mekalanos, Harvard Medical School, Boston, MA, and approved February 8, 2006 (received for review October 27, 2005)

Abstract

We have developed a vaccine strategy for generating an attenuated strain of an intracellular bacterial pathogen that, after uptake by professional antigen-presenting cells, does not replicate intracellularly and is readily killed. However, after degradation of the vaccine strain within the phagolysosome, target antigens are released into the cytosol for endogenous processing and presentation for stimulation of CD8⁺ effector T cells. Applying this strategy to the model intracellular pathogen Listeria monocytogenes, we show that an intracellular replication-deficient vaccine strain is cleared rapidly in normal and immunocompromised animals, yet antigen-specific CD8⁺ effector T cells are stimulated after immunization. Furthermore, animals immunized with the intracellular replication-deficient vaccine strain are resistant to lethal challenge with a virulent WT strain of L. monocytogenes. These studies suggest a general strategy for developing safe and effective, attenuated intracellular replication-deficient vaccine strains for stimulation of protective immune responses against intracellular bacterial pathogens.

Footnotes

^‡To whom correspondence should be addressed. E-mail: dhiggins{at}hms.harvard.edu
Author contributions: H.G.A.B. and D.E.H. designed research; H.G.A.B., C.A.-S., M.J.M., and D.E.H. performed research; N.D.B. and D.E.H. contributed new reagents/analytic tools; H.G.A.B., C.A.-S., M.J.M., and D.E.H. analyzed data; and H.G.A.B. and D.E.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

APC,

antigen-presenting cell;

CFU,

colony-forming units;

BM-MAC,

bone-marrow-derived macrophage;

DC,

dendritic cell;

LLO,

listeriolysin O;

cytoLLO,

cytoplasmic LLO;

Lm,

Listeria monocytogenes;

OVA,

ovalbumin;

SCID,

severe combined immuno-deficient.