This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Li, Z.
Right arrow Articles by Frankel, F. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, Z.
Right arrow Articles by Frankel, F. R.

 Previous Article  |  Next Article 

Infection and Immunity, August 2005, p. 5065-5073, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.5065-5073.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Conditional Lethality Yields a New Vaccine Strain of Listeria monocytogenes for the Induction of Cell-Mediated Immunity

Zhongxia Li,1 Xinyan Zhao,1 Darren E. Higgins,2 and Fred R. Frankel1*

Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1 Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 021152

Received 12 January 2005/ Returned for modification 20 February 2005/ Accepted 10 March 2005

Listeria monocytogenes is a gram-positive intracellular pathogen that can enter phagocytic and nonphagocytic cells and colonize their cytosols. Taking advantage of this property to generate an intracellular vaccine delivery vector, we previously described a mutant strain of L. monocytogenes, {Delta}dal {Delta}dat, which is unable to synthesize cell wall by virtue of deletions in two genes (dal and dat) required for D-alanine synthesis. This highly attenuated strain induced long-lived protective systemic and mucosal immune responses in mice when administered in the transient presence of D-alanine. We have now increased the usefulness of this organism as a vaccine vector by use of an inducible complementation system that obviates the need for exogenous D-alanine administration. The strain expresses a copy of the Bacillus subtilis racemase gene under the control of a tightly regulated isopropyl-ß-D-thiogalactopyranoside (IPTG)-inducible promoter present on a multicopy plasmid. This bacterium demonstrates strict dose-dependent growth in the presence of IPTG. After removal of inducer, bacterial growth ceased within two replication cycles. Following infection of mice in the absence of IPTG or D-alanine, the bacterium survived in vivo for less than 3 days. Nevertheless, a single immunization elicited a state of long-lasting protective immunity against wild-type L. monocytogenes and induced a subset of effector listeriolysin O-specific CD11a+ CD8+ T cells in spleen and other tissues that was strongly enhanced after secondary immunization. This improved L. monocytogenes vector system may have potential use as a live vaccine against human immunodeficiency virus, other infectious diseases, and cancer.

* Corresponding author. Mailing address: 203C Johnson Pavilion, 3610 Hamilton Walk, Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Phone: (215) 898-8730. Fax: (215) 898-9557. E-mail: frankelf{at}mail.med.upenn.edu.

Editor: J. D. Clements

Infection and Immunity, August 2005, p. 5065-5073, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.5065-5073.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Magnani, D. M., Harms, J. S., Durward, M. A., Splitter, G. A. (2009). Nondividing but Metabolically Active Gamma-Irradiated Brucella melitensis Is Protective against Virulent B. melitensis Challenge in Mice. Infect. Immun. 77: 5181-5189 [Abstract] [Full Text]  
  • Yan, L., Qiu, J., Chen, J., Ryan-Payseur, B., Huang, D., Wang, Y., Rong, L., Melton-Witt, J. A., Freitag, N. E., Chen, Z. W. (2008). Selected prfA* Mutations in Recombinant Attenuated Listeria monocytogenes Strains Augment Expression of Foreign Immunogens and Enhance Vaccine-Elicited Humoral and Cellular Immune Responses. Infect. Immun. 76: 3439-3450 [Abstract] [Full Text]  
  • Monk, I. R., Gahan, C. G. M., Hill, C. (2008). Tools for Functional Postgenomic Analysis of Listeria monocytogenes. Appl. Environ. Microbiol. 74: 3921-3934 [Abstract] [Full Text]  
  • Li, Z., Zhao, X., Zhou, C., Gu, B., Frankel, F. R. (2006). A truncated Bacillus subtilis dal gene with a 3' ssrA gene tag regulates the growth and virulence of racemase-deficient Listeria monocytogenes.. Microbiology 152: 3091-3102 [Abstract] [Full Text]  
  • Zhao, X., Zhang, M., Li, Z., Frankel, F. R. (2006). Vaginal Protection and Immunity after Oral Immunization of Mice with a Novel Vaccine Strain of Listeria monocytogenes Expressing Human Immunodeficiency Virus Type 1 gag.. J. Virol. 80: 8880-8890 [Abstract] [Full Text]  
  • Zhao, X., Li, Z., Gu, B., Frankel, F. R. (2005). Pathogenicity and Immunogenicity of a Vaccine Strain of Listeria monocytogenes That Relies on a Suicide Plasmid To Supply an Essential Gene Product. Infect. Immun. 73: 5789-5798 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»