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Infection and Immunity, March 2000, p. 1408-1417, Vol. 68, No. 3
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Interferon Consensus Sequence Binding Protein Confers Resistance against Yersinia enterocolitica

Joachim Hein,1,dagger Volkhard A. J. Kempf,1 Joachim Diebold,2 Nicole Bücheler,1 Sonja Preger,1 Ivan Horak,3 Andreas Sing,1 Uwe Kramer,1 and Ingo B. Autenrieth1,*

Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie1 and Pathologisches Institut,2 Ludwig-Maximilians-Universität, Munich, and Forschungsinstitut für Molekulare Pharmakologie, Abteilung für Molekulare Genetik, Berlin,3 Germany

Received 13 September 1999/Returned for modification 19 October 1999/Accepted 30 November 1999

Interferon consensus sequence binding protein (ICSBP)-deficient mice display enhanced susceptibility to intracellular pathogens. At least two distinct immunoregulatory defects are responsible for this phenotype. First, diminished production of reactive oxygen intermediates in macrophages results in impaired intracellular killing of microorganisms. Second, defective early interleukin-12 (IL-12) production upon microbial challenge leads to a failure in gamma interferon (IFN-gamma ) induction and subsequently in T helper 1 immune responses. Here, we investigated the role of ICSBP in resistance against the extracellular bacterium Yersinia enterocolitica. ICSBP-/- mice failed to produce IL-12 and IFN-gamma , but also IL-4, after Yersinia challenge. In addition, granuloma formation was highly disturbed in infected ICSBP-/- mice, leading to multiple necrotic abscesses in affected organs. Consequently, ICSBP-/- mice rapidly succumbed to acute Yersinia infection. In vitro treatment of spleen cells from ICSBP-/- mice with recombinant IL-12 (rIL-12) or rIL-18 in combination with a second stimulus resulted in IFN-gamma induction. In experimental therapy of infected ICSBP-/- mice, we observed that administration of rIL-12 induced IFN-gamma production which was associated with improved resistance to Yersinia. In contrast, treatment with rIL-18 failed to enhance endogenous IFN-gamma production but nevertheless reduced bacterial burden in ICSBP-/- mice. Although cytokine therapy with rIL-12 or rIL-18 ameliorated the course of Yersinia infection in ICSBP-/- mice, both cytokines failed to completely restore impaired immunity. Taken together, the results indicate that the transcription factor ICSBP is essential for efficient host immune defense against Yersinia. These results are important for understanding the complex host immune responses in bacterial infections.

* Corresponding author. Mailing address: Max von Pettenkofer-Institut, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, D-80336 Munich, Germany. Phone: 49-89-5160-5280. Fax: 49-89-5160-5223. E-mail: autenrieth{at}m3401.mpk.med.uni-muenchen.de.

dagger Present address: Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.

Infection and Immunity, March 2000, p. 1408-1417, Vol. 68, No. 3
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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