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Infect Immun, August 1998, p. 3552-3561, Vol. 66, No. 8
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Pathogenicity and Immunogenicity of a Listeria monocytogenes Strain That Requires D-Alanine for Growth

Robert J. Thompson,1 H. G. Archie Bouwer,2 Daniel A. Portnoy,3 and Fred R. Frankel1 *

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191041; Immunology Research, VA Medical Center, Portland, Oregon 97207, and Earle A. Chiles Research Institute, Providence Medical Center, Portland, Oregon 972032; and Department of Molecular and Cell Biology and School of Public Health, University of California, Berkeley, California 947203

Received 18 December 1997/Returned for modification 11 February 1998/Accepted 13 May 1998

Listeria monocytogenes is an intracellular bacterial pathogen that elicits a strong cellular immune response following infection and therefore has potential use as a vaccine vector. However, while infections by L. monocytogenes are fairly rare and can readily be controlled by a number of antibiotics, the organism can nevertheless cause meningitis and death, particularly in immunocompromised or pregnant patients. We therefore have endeavored to isolate a highly attenuated strain of this organism for use as a vaccine vector. D-Alanine is required for the synthesis of the mucopeptide component of the cell walls of virtually all bacteria and is found almost exclusively in the microbial world. We have found in L. monocytogenes two genes that control the synthesis of this compound, an alanine racemase gene (dal) and a D-amino acid aminotransferase gene (dat). By inactivating both genes, we produced an organism that could be grown in the laboratory when supplemented with D-alanine but was unable to grow outside the laboratory, particularly in the cytoplasm of eukaryotic host cells, the natural habitat of this organism during infection. In mice, the double-mutant strain was completely attenuated. Nevertheless, it showed the ability, particularly under conditions of transient suppression of the mutant phenotype, to induce cytotoxic T-lymphocyte responses and to generate protective immunity against lethal challenge by wild-type L. monocytogenes equivalent to that induced by the wild-type organism.

* Corresponding author. Mailing address: 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.

Infect Immun, August 1998, p. 3552-3561, Vol. 66, No. 8
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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Copyright © 1998 by the American Society for Microbiology. All rights reserved.