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Infection and Immunity, February 2001, p. 1072-1083, Vol. 69, No. 2
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.2.1072-1083.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Parameters Underlying Successful Protection with Live Attenuated Mutants in Experimental Shigellosis

Maria Lina Bernardini,1,* Josette Arondel,2 Irene Martini,1 Awa Aidara,3 and Philippe J. Sansonetti2

Dipartimento di Biologia Cellulare e dello Sviluppo, Sezione di Scienze Microbiologiche, and Istituto Pasteur Fondazione Cenci Bolognetti, Università `La Sapienza,' 00185 Rome, Italy1; Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France2; and Laboratoire de Bactériologie Expérimentale, Institut Pasteur de Dakar, Dakar, Senegal3

Received 5 July 2000/Returned for modification 31 August 2000/Accepted 25 October 2000

Because the use of live attenuated mutants of Shigella spp. represents a promising approach to protection against bacillary dysentery (M. E. Etherridge, A. T. M. Shamsul Hoque, and D. A. Sack, Lab. Anim. Sci. 46:61-66, 1996), it becomes essential to rationalize this approach in animal models in order to optimize attenuation of virulence in the vaccine candidates, as well as their route and mode of administration, and to define the correlates of protection. In this study, we have compared three strains of Shigella flexneri 5---the wild-type M90T, an aroC mutant, and a double purE aroC mutant---for their pathogenicity, immunogenicity, and protective capacity. Protection against keratoconjunctivitis, induced by wild-type M90T, was used as the protection read out in guinea pigs that were inoculated either intranasally or intragastrically. Following intranasal immunization, the aroC mutant elicited weak nasal tissue destruction compared to M90T and achieved protection correlated with high levels of local anti-lipopolysaccharide immunoglobulin A (IgA), whereas the purE aroC double mutant, which also elicited weak tissue destruction, was not protective and elicited a low IgA response. Conversely, following intragastric immunization, only the M90T purE aroC double mutant elicited protection compared to both the aroC mutant and the wild-type strain. This mutant caused mild inflammatory destruction, particularly at the level of Peyer's patches, but it persisted much longer within the tissues. This could represent an essential parameter of the protective response that, in this case, did not clearly correlate with high anti-lipopolysaccharide IgA titers.

* 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: 3906 49917579. Fax: 3906 49917594. E-mail: bernardini{at}axcasp.caspur.it.

Infection and Immunity, February 2001, p. 1072-1083, Vol. 69, No. 2
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.2.1072-1083.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.