Interferon Consensus Sequence Binding Protein Confers Resistance againstYersinia enterocolitica

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Abstract
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-γ) induction and subsequently in T helper 1 immune responses. Here, we investigated the role of ICSBP in resistance against the extracellular bacteriumYersinia enterocolitica. ICSBP−/−mice failed to produce IL-12 and IFN-γ, but also IL-4, afterYersiniachallenge. 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 acuteYersiniainfection. 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-γ induction. In experimental therapy of infected ICSBP−/−mice, we observed that administration of rIL-12 induced IFN-γ production which was associated with improved resistance toYersinia. In contrast, treatment with rIL-18 failed to enhance endogenous IFN-γ production but nevertheless reduced bacterial burden in ICSBP−/−mice. Although cytokine therapy with rIL-12 or rIL-18 ameliorated the course ofYersiniainfection 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 againstYersinia. These results are important for understanding the complex host immune responses in bacterial infections.