Interferon consensus sequence binding protein confers resistance against Yersinia enterocolitica

Interferon consensus sequence binding protein (ICSBP)-deficient mice displa y enhanced susceptibility to intracellular pathogens. At least two distinct immunoregulatory defects are responsible for this phenotype. First, dimini shed production of reactive oxygen intermediates in macrophages results in impaired intracellular killing of microorganisms. Second, defective early i nterleukin-12 (IL-12) production upon microbial challenge leads to a failur e in gamma interferon (IFN-gamma) induction and subsequently in T helper I immune responses. Here, we investigated the role of ICSBP in resistance aga inst the extracellular bacterium Yersinia enterocolitica. ICSBP-/- mice fai led 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. Conseque ntly, ICSBP-/- mite rapidly succumbed to acute Yersinia infection. In vitro treatment of spleen cells from ICSBP-/- mice with recombinant IL-12 (rIL-1 2) or rIL-18 in combination with a second stimulus resulted in IFN-gamma in duction. In experimental therapy of infected ICSBP-/- mice, we observed tha t administration of rIL-12 induced IFN-gamma production which was associate d 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 e fficient host immune defense against Yersinia. These results are important for understanding the complex host immune responses in bacterial infections .