Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor deficient mice

Mice with a targeted disruption of the interferon gamma receptor gene (IFN-gamma R0/0 mice) and control wild-type mice were inoculated with the Bacillus Calmette-Guérin (BCG) strain of Mycobacterium bovis. BCG infection was not lethal for wild-type mice whereas all IFN-gamma R0/0 mice died approximately 7-9 wk after inoculation. Histological examination at 2 and 6 wk after BCG inoculation showed that livers of IFN-gamma R0/0 mice had higher numbers of acid-fast bacteria than wild-type mice, especially at 6 wk. In parallel, the livers of IFN-gamma R0/0 mice showed a reduction in the formation of characteristic granulomas at 2 wk after inoculation. Injection of lipopolysaccharide (LPS) 2 wk after BCG inoculation was significantly less lethal for IFN-gamma R0/0 mice than for wild-type mice. Reduced lethality of LPS correlated with a drastically reduced production of tumor necrosis factor alpha (TNF-alpha) in the IFN-gamma R0/0 mice. Interleukin 1 alpha (IL-1 alpha) and IL-6 levels in the serum were also significantly reduced in the IFN-gamma R0/0 mice after BCG infection and LPS challenge. The greatly reduced capacity of BCG-infected IFN-gamma R0/0 mice to produce TNF-alpha may be an important factor in their inability to resist BCG infection. These results show that the presence of a functional IFN-gamma receptor is essential for the recovery of mice from BCG infection, and that IFN-gamma is a key element in the complex process whereby BCG infection leads to the sensitization to endotoxin.

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Mouse Gamma Herpesvirus MHV-68 Induces Severe Gastrointestinal (GI) Dilatation in Interferon Gamma Receptor-Deficient Mice (IFNγR−/−) That Is Blocked by Interleukin-10

Viruses ◽

10.3390/v10100518 ◽

2018 ◽

Vol 10 (10) ◽

pp. 518 ◽

Cited By ~ 1

Author(s):

Hao Chen ◽

Mee Bartee ◽

Jordan Yaron ◽

Liying Liu ◽

Liqiang Zhang ◽

...

Keyword(s):

Interferon Gamma ◽

Interleukin 1 ◽

Pulmonary Hemorrhage ◽

Interleukin 10 ◽

Necrosis Factor Alpha ◽

Gamma Receptor ◽

Gamma Herpesvirus ◽

Factor Alpha ◽

Gi Inflammation ◽

Deficient Mice

Inflammatory bowel disease (IBD) and Clostridium difficile infection cause gastrointestinal (GI) distension and, in severe cases, toxic megacolon with risk of perforation and death. Herpesviruses have been linked to severe GI dilatation. MHV-68 is a model for human gamma herpesvirus infection inducing GI dilatation in interleukin-10 (IL-10)-deficient mice but is benign in wildtype mice. MHV-68 also causes lethal vasculitis and pulmonary hemorrhage in interferon gamma receptor-deficient (IFNγR−/−) mice, but GI dilatation has not been reported. In prior work the Myxomavirus-derived anti-inflammatory serpin, Serp-1, improved survival, reducing vasculitis and pulmonary hemorrhage in MHV-68-infected IFNγR−/− mice with significantly increased IL-10. IL-10 has been investigated as treatment for GI dilatation with variable efficacy. We report here that MHV-68 infection produces severe GI dilatation with inflammation and gut wall degradation in 28% of INFγR-/- mice. Macrophage invasion and smooth muscle degradation were accompanied by decreased concentrations of T helper (Th2), B, monocyte, and dendritic cells. Plasma and spleen IL-10 were significantly reduced in mice with GI dilatation, while interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNFα) and INFγ increased. Treatment of gamma herpesvirus-infected mice with exogenous IL-10 prevents severe GI inflammation and dilatation, suggesting benefit for herpesvirus-induced dilatation.

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Increased liver damage after bile duct ligation in interferon-gamma receptor deficient mice: Interferon-gamma as a protective factor

Gastroenterology ◽

10.1016/s0016-5085(00)86210-1 ◽

2000 ◽

Vol 118 (4) ◽

pp. A1014

Author(s):

Tom van der Poll ◽

Fiebo J. ten Kate ◽

Sander J. van Deventer ◽

Miguel E. Sewnath ◽

Huug Obertop ◽

...

Keyword(s):

Bile Duct ◽

Interferon Gamma ◽

Liver Damage ◽

Protective Factor ◽

Bile Duct Ligation ◽

Gamma Receptor ◽

Duct Ligation ◽

Deficient Mice

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The course of Plasmodium chabaudi chabaudi infections in interferon‐gamma receptor deficient mice

Parasite Immunology ◽

10.1046/j.1365-3024.1997.d01-227.x ◽

1997 ◽

Vol 19 (8) ◽

pp. 375-383 ◽

Cited By ~ 59

Author(s):

NICOLAS FAVRE ◽

BERNHARD RYFFEL ◽

GÉRARD BORDMANN ◽

WERNER RUDIN

Keyword(s):

Interferon Gamma ◽

Plasmodium Chabaudi ◽

Gamma Receptor ◽

Deficient Mice

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Irgm1 Is a Negative Regulator of Interferon-Gamma Signaling in Hematopoietic Stem Cells.

Blood ◽

10.1182/blood.v114.22.382.382 ◽

2009 ◽

Vol 114 (22) ◽

pp. 382-382 ◽

Cited By ~ 1

Author(s):

Katherine Y King ◽

Megan T Baldridge ◽

David C Weksberg ◽

Margaret A Goodell

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Interferon Gamma ◽

Negative Regulator ◽

Wild Type ◽

Self Renewal ◽

Hematopoietic Stem ◽

Knock Out ◽

Deficient Mice

Abstract Abstract 382 Hematopoietic stem cells (HSCs) are a self-renewing population of bone marrow cells that give rise to all of the cellular elements of the blood and retain enormous proliferative potential in vivo. We have a growing understanding that the controls on HSC proliferation are tied in part to regulation by the immune system—specifically, that HSC proliferation and mobilization can be stimulated by the immune cytokines interferon-alpha and interferon-gamma (IFNg). Our previous work has demonstrated that HSC quiescence and function are aberrant in mice lacking the immunity-related GTPase Irgm1 (also Lrg47). Indeed, the bone marrow of Irgm1-deficient animals at baseline mimics the bone marrow of wild type animals that have been stimulated with IFNg. We hypothesized that the HSC defects in Irgm1-deficient animals are due to overabundant IFNg signaling, and that Irgm1 normally serves to dampen the stimulatory effects of IFNg on HSCs. To test this hypothesis, we used RNA expression profiling to compare gene expression in wild type versus Irgm1-deficient mice. We found that interferon-dependent signaling is globally upregulated in the HSCs of Irgm1-deficient mice. Next we generated Irgm1-/-IFNgR1-/- and Irgm1-/-Stat1-/- double knock out animals. In contrast to the phenotype of Irgm1 single knock out mutants, the hyperproliferation and self-renewal defects in HSCs were both rescued in the double knock out animals, indicating that IFNg signaling is required for manifestation of the Irgm1-deficient phenotype. Futhermore, we found that Irgm1 is expressed in HSCs in a Stat1- and IFNgR-dependent fashion, suggesting that it forms a negative feedback loop for IFNg signaling in the HSC population. Collectively, our results indicate that Irgm1 is a powerful negative regulator of IFNg-dependent stimulation in HSCs. These findings demonstrate that IFNg provides a significant stimulus for HSC proliferation even in the absence of infection, and that IFNg-dependent signaling must be tightly regulated to preserve HSC self-renewal capacity. This study provides evidence that the Irgm1 protein can serve as a link between immunity and regulation of hematopoiesis at the level of the stem cell. We speculate that utilization of Irgm1 for its immune functions may detract from its ability to regulate HSC self-renewal capacity, thus ultimately contributing to myelosuppression and increased risk of death from chronic infections such as tuberculosis. Disclosures: No relevant conflicts of interest to declare.

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Interferon gamma receptor deficient mice are resistant to endotoxic shock.

Journal of Experimental Medicine ◽

10.1084/jem.179.5.1437 ◽

1994 ◽

Vol 179 (5) ◽

pp. 1437-1444 ◽

Cited By ~ 209

Author(s):

B D Car ◽

V M Eng ◽

B Schnyder ◽

L Ozmen ◽

S Huang ◽

...

Keyword(s):

Interferon Gamma ◽

Binding Capacity ◽

Endotoxic Shock ◽

Lethal Dose ◽

Mutant Mice ◽

Wild Type ◽

Similar Reduction ◽

Ifn Gamma ◽

Gamma Receptor ◽

Lps Binding

Antibody neutralization studies have established interferon gamma (IFN-gamma) as a critical mediator of endotoxic shock. The advent of IFN-gamma receptor negative (IFN gamma R-/-) mutant mice has enabled a more direct assessment of the role of IFN-gamma in endotoxin (lipopolysaccharide [LPS]-induced shock. We report that IFN gamma R-/- mice have an increased resistance to LPS-induced toxicity, this resistance manifesting well before the synthesis and release of LPS-induced IFN-gamma. LPS-induced lymphopenia, thrombocytopenia, and weight loss seen in wild-type mice were attenuated in IFN gamma R-/- mice. IFN gamma R-/- mice tolerated 100-1,000 times more LPS than the minimum lethal dose for wild-type mice in a D-galactosamine (D-GalN)/LPS model. Serum tumor necrosis factor (TNF) levels were 10-fold reduced in mutant mice given LPS or LPS/D-GalN. Bone marrow and splenic macrophages from IFN gamma R-/- mice had a four- to sixfold decreased LPS-binding capacity which correlated with similar reduction in CD14. Serum from mutant mice reduced macrophage LPS binding by a further 50%, although LPS binding protein was only 10% reduced. The expression of TNF receptor I (p55) and II (p75) was identical between wild-type and mutant mice. Thus, depressed TNF synthesis, diminished expression of CD14, and low plasma LPS-binding capacity, in addition to blocked IFN-gamma signaling in the mutant mice, likely to combine to manifest in the resistant phenotype of IFN gamma R-/- mice to endotoxin.

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