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Crucial role of interferon consensus sequence binding protein, but neither of interferon regulatory factor 1 nor of nitric oxide synthesis for protection against murine listeriosis.

Fehr T, Schoedon G, Odermatt B, Holtschke T, Schneemann M, Bachmann MF, Mak TW, Horak I, Zinkernagel RM - J. Exp. Med. (1997)

Bottom Line: However, the involved signaling pathways and effector mechanisms are still poorly understood.This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-gamma in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-gamma stimulation, whereas nitric oxide production was normal.These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-gamma-mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Immunology, University Hospital, Zürich, Switzerland.

ABSTRACT
Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF) 1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP-/- and to a lesser degree also IRF2-/- mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-gamma in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-gamma stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-gamma-mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

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Capacity of ICSBP−/− spleen cells to transfer Listeria resistance to RAG2−/− mice. Non adherent spleen cells of ICSBP+/+ (open diamonds) or ICSBP−/− (filled diamonds) mice were transferred to RAG2−/−  mice. After 24 h the recipients as well as untreated RAG2−/− mice (open  circles) were infected with 2 × 105 CFU of Listeria, and bacterial titers were  determined on day 9 after infection to assess overall protection. Groups of  four to five recipient mice were used. Each symbol represents one mouse.  One of three comparable experiments is shown.
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Figure 2: Capacity of ICSBP−/− spleen cells to transfer Listeria resistance to RAG2−/− mice. Non adherent spleen cells of ICSBP+/+ (open diamonds) or ICSBP−/− (filled diamonds) mice were transferred to RAG2−/− mice. After 24 h the recipients as well as untreated RAG2−/− mice (open circles) were infected with 2 × 105 CFU of Listeria, and bacterial titers were determined on day 9 after infection to assess overall protection. Groups of four to five recipient mice were used. Each symbol represents one mouse. One of three comparable experiments is shown.

Mentions: RAG2−/− mice are devoid of functional T and B cells, but have normal macrophages and natural killer cells (47). When infected with an intermediate dose of Listeria, they are able to control bacterial replication comparable to nude mice (46), but cannot eliminate the pathogen. To test whether ICSBP-deficient T cells could develop normal specific anti- Listeria immunity, we transferred on day 0 macrophage- depleted ICSBP−/− spleen cells into RAG2−/− mice, challenged them with a high dose of Listeria (2 × 105 CFU i.v.) on day 1 and evaluated Listeria titers in liver and spleen on day 10 to look for efficiency of the specific immune response. As a positive control normal spleen cells and as a negative control no spleen cells were transferred. The result (Fig. 2) revealed no difference of Listeria counts between recipients of ICSBP−/− and ICSBP+/+ spleen cells; in contrast RAG2−/− mice that did not receive spleen cells exhibited 100- (spleen) to 1,000-fold (liver) higher bacterial counts. This result indicates that ICSBP−/− splenocytes (especially the mutant T cells) were able to promote elimination of Listeria as successfully as normal lymphocytes in cooperation with the intact macrophage compartment of the RAG2−/− mouse.


Crucial role of interferon consensus sequence binding protein, but neither of interferon regulatory factor 1 nor of nitric oxide synthesis for protection against murine listeriosis.

Fehr T, Schoedon G, Odermatt B, Holtschke T, Schneemann M, Bachmann MF, Mak TW, Horak I, Zinkernagel RM - J. Exp. Med. (1997)

Capacity of ICSBP−/− spleen cells to transfer Listeria resistance to RAG2−/− mice. Non adherent spleen cells of ICSBP+/+ (open diamonds) or ICSBP−/− (filled diamonds) mice were transferred to RAG2−/−  mice. After 24 h the recipients as well as untreated RAG2−/− mice (open  circles) were infected with 2 × 105 CFU of Listeria, and bacterial titers were  determined on day 9 after infection to assess overall protection. Groups of  four to five recipient mice were used. Each symbol represents one mouse.  One of three comparable experiments is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196174&req=5

Figure 2: Capacity of ICSBP−/− spleen cells to transfer Listeria resistance to RAG2−/− mice. Non adherent spleen cells of ICSBP+/+ (open diamonds) or ICSBP−/− (filled diamonds) mice were transferred to RAG2−/− mice. After 24 h the recipients as well as untreated RAG2−/− mice (open circles) were infected with 2 × 105 CFU of Listeria, and bacterial titers were determined on day 9 after infection to assess overall protection. Groups of four to five recipient mice were used. Each symbol represents one mouse. One of three comparable experiments is shown.
Mentions: RAG2−/− mice are devoid of functional T and B cells, but have normal macrophages and natural killer cells (47). When infected with an intermediate dose of Listeria, they are able to control bacterial replication comparable to nude mice (46), but cannot eliminate the pathogen. To test whether ICSBP-deficient T cells could develop normal specific anti- Listeria immunity, we transferred on day 0 macrophage- depleted ICSBP−/− spleen cells into RAG2−/− mice, challenged them with a high dose of Listeria (2 × 105 CFU i.v.) on day 1 and evaluated Listeria titers in liver and spleen on day 10 to look for efficiency of the specific immune response. As a positive control normal spleen cells and as a negative control no spleen cells were transferred. The result (Fig. 2) revealed no difference of Listeria counts between recipients of ICSBP−/− and ICSBP+/+ spleen cells; in contrast RAG2−/− mice that did not receive spleen cells exhibited 100- (spleen) to 1,000-fold (liver) higher bacterial counts. This result indicates that ICSBP−/− splenocytes (especially the mutant T cells) were able to promote elimination of Listeria as successfully as normal lymphocytes in cooperation with the intact macrophage compartment of the RAG2−/− mouse.

Bottom Line: However, the involved signaling pathways and effector mechanisms are still poorly understood.This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-gamma in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-gamma stimulation, whereas nitric oxide production was normal.These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-gamma-mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Immunology, University Hospital, Zürich, Switzerland.

ABSTRACT
Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF) 1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP-/- and to a lesser degree also IRF2-/- mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-gamma in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-gamma stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-gamma-mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

Show MeSH
Related in: MedlinePlus