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Infection and Immunity, December 2003, p. 7002-7013, Vol. 71, No. 12
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.12.7002-7013.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Analysis of Virulence and Inflammatory Potential of Shigella flexneri Purine Biosynthesis Mutants

Antonella Cersini,1 Maria Celeste Martino,1 Irene Martini,1 Giacomo Rossi,2 and Maria Lina Bernardini1*

Dipartimento di Biologia Cellulare e dello Sviluppo, Sezione di Scienze Microbiologiche, Università La Sapienza, 00185 Rome,1 Facoltà di Medicina Veterinaria, Università di Camerino, 62032 Matelica, Italy2

Received 24 March 2003/ Returned for modification 24 June 2003/ Accepted 8 September 2003

Several Shigella flexneri mutants with defects in aromatic amino acid and/or purine biosynthesis have been evaluated as vaccines in humans or in animal models. To be suitable as a vaccine, a mutant has to show virulence attenuation, minimal reactogenicity, and a good immunogenic potential in animal models. With this aim, we have constructed five S. flexneri 5 (wild-type strain M90T) mutants with inactivation of one or two of the loci purEK, purHD, and guaBA, governing early or late steps of purine biosynthesis. The mutants have been analyzed in vitro in cell cultures and in vivo in the Sereny test and in the murine pulmonary model of shigellosis. M90T guaBA, M90T guaBA purEK, M90T guaBA purHD, and M90T purHD purEK gave a negative result in the Sereny test. In contrast, in the murine pulmonary model all of the strains had the same 50% lethal dose as the wild type, except M90T guaBA purHD, which did not result in death of the animals. Nevertheless, bacterial counts in infected lungs, immunohistochemistry, and reverse transcription-PCR analysis of mRNAs for tumor necrosis factor alpha (TNF-{alpha}), gamma interferon (IFN-{gamma}), interleukin-1ß (IL-1ß), IL-6, IL-12, and inducible nitric oxide synthase (iNOS) revealed significant differences among the strains. At 72 h postinfection, M90T guaBA purHD still induced proinflammatory cytokines and factors such as IL-1ß, IL-6, TNF-{alpha}, and iNOS, along with cytokines such as IL-12 and IFN-{gamma}. Moreover, in the absence of evident lesions in murine tissues, this mutant highly stimulated major histocompatibility complex class II expression, showing a significant ability to activate the innate immunity of the host.

* Corresponding author. Mailing address: Dipartimento di Biologia Cellulare e dello Sviluppo, Sezione di Scienze Microbiologiche, Università ‘La Sapienza,' Via dei Sardi 70, 00185 Rome, Italy. Phone: 39 06 49917579/49917850. Fax: 39 06 49917594. E-mail: MariaLina.Bernardini{at}uniroma1.it.

Editor: A. D. O'Brien

Infection and Immunity, December 2003, p. 7002-7013, Vol. 71, No. 12
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.12.7002-7013.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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