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Infection and Immunity, March 1999, p. 1093-1099, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Pathogenicity Island 2 Mutants of Salmonella typhimurium Are Efficient Carriers for Heterologous Antigens and Enable Modulation of Immune Responses

Eva Medina,1 Paola Paglia,2 Thomas Nikolaus,3 Astrid Müller,1 Michael Hensel,3 and Carlos A. Guzmán1,*

Department of Microbial Pathogenicity and Vaccine Research, Division of Microbiology, GBF-National Research Centre for Biotechnology, D-38124 Braunschweig,1 and Lehrstuhl für Bakteriologie, Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, D-80336 Munich,3 Germany, and Experimental Immunotherapy and Gene Therapy Unit, Istituto Nazionale per Lo Studio e la Cura dei Tumori, I-20133 Milano, Italy2

Received 10 August 1998/Returned for modification 20 October 1998/Accepted 29 December 1998

The potential use as vaccine delivery system of Salmonella typhimurium strains harboring defined mutations in the sseC (HH104) and sseD (MvP101) genes, which encode putative effector proteins of the type III secretion system of Salmonella pathogenicity island 2, was evaluated and compared with that of the well-characterized aroA mutant strain SL7207 by using beta -galactosidase (beta -Gal) as a model antigen. When orally administered to immune-competent or gamma interferon-deficient (IFN-gamma -/-) BALB/c mice, both mutants were found to be highly attenuated (50% lethal dose, >109 bacteria). Both strains were also able to efficiently colonize and persist in Peyer's patches. Immunization with HH104 and MvP101 triggered beta -Gal-specific serum and mucosal antibody responses equivalent to or stronger than those observed in SL7207-immunized mice. Although immunoglobulin G2 (IgG2) serum antibodies were dominant in all groups, IgG1 was also significantly increased in mice vaccinated with MvP101 and SL7207. Comparable beta -Gal-specific IgA and IgG antibodies were detected in intestinal lavages from mice immunized with the different strains. Antigen-specific CD4+ T-helper cells were generated after vaccination with all vaccine prototypes; however, responses were significantly more efficient when HH104 and MvP101 were used (P < 0.05). Significantly higher levels of IFN-gamma were produced by restimulated spleen cells from mice immunized with HH104 than from those vaccinated with the MvP101 or SL7207 derivatives (P <=  0.05). Interestingly, the three strains induced major histocompatibility complex class I-restricted CD8+ cytotoxic T cells against beta -Gal; however, cytotoxic T-lymphocyte responses were significantly stronger after immunization with HH104 (P < 0.05). These novel S. typhimurium attenuated strains constitute promising delivery systems for vaccine antigens. The qualitative differences observed in the obtained responses with different carriers may be useful for those applications in which a targeted immunomodulation is required.

* Corresponding author. Mailing address: Department of Microbial Pathogenicity and Vaccine Research, Division of Microbiology, GBF-National Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany. Phone: 49-531-6181558. Fax: 49-531-6181411. E-mail: cag{at}gbf.de.

Infection and Immunity, March 1999, p. 1093-1099, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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