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Infection and Immunity, April 2003, p. 1804-1812, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.1804-1812.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Attenuated Yersinia enterocolitica Mutant Strains Exhibit Differential Virulence in Cytokine-Deficient Mice: Implications for the Development of Novel Live Carrier Vaccines

María S. Di Genaro,1 Marc Waidmann,1 Uwe Kramer,1,2 Niclas Hitziger,1,2 Erwin Bohn,1,2 and Ingo B. Autenrieth1,2*

Max von Pettenkofer Institute for Hygiene and Medical Microbiology, Ludwig Maximilians University Munich, 80336 Munich,1 Institut für Medizinische Mikrobiologie, Universitätsklinikum Tübingen, Tübingen, Germany2

Received 4 October 2002/ Returned for modification 20 December 2002/ Accepted 14 January 2003

Yersinia enterocolitica mutant strains, including mutants deficient in the chaperone SycH resulting in a functional deficiency in tyrosine phosphatase (YopH), Mn-cofactored superoxide dismutase (SodA), iron-repressive protein 1 (IRP-1), and Yersinia adhesin A (YadA), were demonstrated to be highly attenuated in wild-type C57BL/6 mice. TNFRp55-/-, IL-12p40-/-, and IL-18-/- mutant mice, in which the Yersinia wild-type strain causes severe systemic infections, were used to investigate whether these Yersinia mutant strains would be attenuated in immunodeficient hosts. A plasmid-cured Yersinia mutant strain was unable to colonize any of the mutant mice tested. A SycH-deficient mutant strain colonized intestinal tissues of these mice but was attenuated for systemic infection in all of the mutant mice. Both YadA- and Irp-1-deficient Yersinia mutants were still attenuated in IL-12-/- and IL-18-/- mice but were pathogenic in TNFRp55-/- mice. By contrast, a Yersinia sodA mutant was highly pathogenic for TNFRp55-/- and IL-12p40-/- mice while interleukin-18 (IL-18) was dispensable. This finding demonstrates that certain virulence factors enable yersiniae to compete with distinct cytokine-dependent host defense mechanisms. Moreover, while gamma interferon mRNA expression did not reflect protective host responses in cytokine-deficient mice, IL-10 expression coincided with a heavy splenic bacterial load and was associated with progressive infection courses. We can thus segregate minor (SodA), intermediate (YadA and IRP-1), and major (YopH) virulence factors of Y. enterocolitica. Finally, we demonstrate that, even in immunocompromised hosts, Yersinia sycH and, with some restrictions, irp-1 mutants may be suitable for use as live carrier vaccines.

* Corresponding author. Mailing address: Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Universitätsklinikum Tübingen, Elfriede-Aulhorn-Str. 6, D-72076 Tübingen, Germany. Phone: 49-7071-29 82351. Fax: 49-7071-29 5440. E-mail: Ingo.Autenrieth{at}med.uni-tuebingen.de.

Editor: J. T. Barbieri

Infection and Immunity, April 2003, p. 1804-1812, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.1804-1812.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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