Inactivation of Lrg-47 and Irg-47 Reveals a Family of Interferon γ–Inducible Genes with Essential, Pathogen-Specific Roles in Resistance to Infection

The cytokine interferon (IFN)-γ regulates immune clearance of parasitic, bacterial, and viral infections; however, the underlying mechanisms are poorly understood. Recently, a family of IFN-γ–induced genes has been identified that encode 48-kD GTP-binding proteins that localize to the endoplasmic reticulum of cells. The prototype of this family, IGTP, has been shown to be required for host defense against acute infections with the protozoan parasite Toxoplasma gondii, but not for normal clearance of the bacterium Listeria monocytogenes and murine cytomegalovirus (MCMV). To determine whether other members of the gene family also play important roles in immune defense, we generated mice that lacked expression of the genes LRG-47 and IRG-47, and examined their responses to representative pathogens. After infection with T. gondii, LRG-47–deficient mice succumbed uniformly and rapidly during the acute phase of the infection; in contrast, IRG-47–deficient mice displayed only partially decreased resistance that was not manifested until the chronic phase. After infection with L. monocytogenes, LRG-47–deficient mice exhibited a profound loss of resistance, whereas IRG-47–deficient mice exhibited completely normal resistance. In addition, both strains displayed normal clearance of MCMV. Thus, LRG-47 and IRG-47 have vital, but distinct roles in immune defense against protozoan and bacterial infections.

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Hematopoietic Remodeling in Interferon-γ–Deficient Mice Infected With Mycobacteria

Blood ◽

10.1182/blood.v91.8.2914.2914_2914_2924 ◽

1998 ◽

Vol 91 (8) ◽

pp. 2914-2924 ◽

Cited By ~ 60

Author(s):

Peter J. Murray ◽

Richard A. Young ◽

George Q. Daley

Keyword(s):

Immune Response ◽

T Cell ◽

Bacterial Infections ◽

Mycobacterial Infection ◽

Interferon Γ ◽

T Cell Response ◽

Cell Phenotype ◽

Hematopoietic Tissue ◽

Ifn Γ ◽

Deficient Mice

Control of intracellular bacterial infections requires interferon-γ (IFN-γ) both for establishing a Th1 T-cell response and for activating macrophages to kill the bacteria. Exposure of mice deficient in IFN-γ to mycobacterial infection produces an immune response characterized by a Th2 T-cell phenotype, florid bacterial growth, and death. We report here that IFN-γ–deficient mice infected with mycobacteria also undergo a dramatic remodeling of the hematopoietic system. Myeloid cell proliferation proceeds unchecked throughout the course of mycobacterial infection, resulting in a transition to extramedullary hematopoiesis. The splenic architecture of infected IFN-γ–deficient mice is completely effaced by expansion of macrophages, granulocytes, and extramedullary hematopoietic tissue. These features coincide with splenomegaly, an increase in splenic myeloid colony-forming activity, and marked granulocytosis in the peripheral blood. Systemic levels of cytokines are elevated, particularly interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF). These results suggest that in addition to its central role in cellular immunity, IFN-γ may be a key cytokine in coordinate regulation of immune effector cells and myelopoiesis. This model should be valuable for deciphering the cross-talk between the immune response and hematopoiesis during bacterial infection and for improving our understanding of the mechanisms that control chronic infections.

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Abstract 116: Detrimental Role of Toll-Like Receptor 4 in Cardiovirus-Induced Myocarditis

Circulation Research ◽

10.1161/res.111.suppl_1.a116 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Fumitaka Sato ◽

Seiichi Omura ◽

Nicholas E Martinez ◽

Eiichiro Kawai ◽

Ganta V Chaitanya ◽

...

Keyword(s):

Immune Responses ◽

Acute Phase ◽

Viral Entry ◽

Viral Myocarditis ◽

Chronic Phase ◽

Enzyme Linked Immunosorbent Assay ◽

Tlr4 Ligand ◽

Ifn Γ ◽

Deficient Mice

Picornavirus infections have been known as a leading cause of viral myocarditis in humans. Theiler’s murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae and was reported to cause inflammation in the heart in one manuscript, while its pathomechanism is unclear. In viral myocarditis, viral replication in the heart and/or immune responses against virus as well as heart-antigen (autoimmunity) can contribute to the pathogenesis. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that are important for recognizing pathogens as well as triggering innate immunity. Among TLRs, TLR4 has been demonstrated to play important roles in virus-mediated pathology: 1) TLR4 can contribute to viral entry in some viruses, 2) TLR4 may mediate tissue damage by anti-virus immune responses (immunopathology), 3) high levels of TLR4 expression were observed in the heart of patients with dilated cardiomyopathy following acute viral myocarditis, and 4) some viruses can bind to lipopolysaccharide (LPS), which is a TLR4 ligand. To determine the role of TLR4 in TMEV-induced myocarditis, we infected male C3H/HeJ (TLR4-deficient) and C3H/HeNtac (control TLR4+) mice with the DA strain of TMEV. We harvested the hearts and spleens on days 6 and 7 (acute phase) or days 63 and 64 (chronic phase) post-infection. Cardiac pathology was evaluated by hematoxylin and eosin staining and production of pro-inflammatory cytokines, interleukin (IL)-17A and interferon (IFN)-γ, from spleen cells was measured by an enzyme-linked immunosorbent assay (ELISA). In both mice, mild myocarditis was observed during the acute phase of TMEV infection. During the chronic phase, both mice developed severe pathology in the heart, including basophilic degeneration and calcification. However, the incidence of myocarditis was higher in control mice than TLR4-deficient mice. IL-17A and IFN-γ production was higher in control mice than in TLR4-deficient mice (control vs. TLR4-deficient mice, acute phase: IL-17A, 196 vs. 146 pg/ml; IFN-γ, 72 vs. 39 ng/ml; chronic phase: IL-17A, 290 vs. 229 pg/ml; IFN- γ, 142 vs. 88 ng/ml). These results suggest that TLR4 may be detrimental in TMEV-induced myocarditis by increasing pro-inflammatory cytokine production.

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Gamma Interferon Produced by Antigen-Specific CD4+ T Cells Regulates the Mucosal Immune Responses to Citrobacter rodentium Infection

Infection and Immunity ◽

10.1128/iai.01343-09 ◽

2010 ◽

Vol 78 (6) ◽

pp. 2653-2666 ◽

Cited By ~ 45

Author(s):

Hideyuki Shiomi ◽

Atsuhiro Masuda ◽

Shin Nishiumi ◽

Masayuki Nishida ◽

Tetsuya Takagawa ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Gamma Interferon ◽

Immune Defense ◽

Interleukin 4 ◽

Mucosal Inflammation ◽

Citrobacter Rodentium ◽

Macrophage Phagocytosis ◽

Ifn Γ ◽

Deficient Mice

ABSTRACT Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the surface of intestinal epithelial cells and causes mucosal inflammation. This bacterium is an ideal model for investigating pathogen-host immune interactions in the gut. It is well known that gene transcripts for Th1 cytokines are highly induced in colonic tissue from mice infected with C. rodentium. However, it remains to be seen whether the Th1 or Th2 cytokines produced by antigen-specific CD4+ T cells provide effective regulation of the host immune defense against C. rodentium infection. To investigate the antigen-specific immune responses, C. rodentium expressing ovalbumin (OVA-C. rodentium), a model antigen, was generated and used to define antigen-specific responses under gamma interferon (IFN-γ)-deficient or interleukin-4 (IL-4)-deficient conditions in vivo. The activation of antigen-specific CD4+ T cells and macrophage phagocytosis were evaluated in the presence of IFN-γ or IL-4 in vitro. IFN-γ-deficient mice exhibited a loss of body weight and a higher bacterial concentration in feces during OVA-C. rodentium infection than C57BL/6 (wild type) or IL-4-deficient mice. This occurred through the decreased efficiency of macrophage phagocytosis and the activation of antigen-specific CD4+ T cells. Furthermore, a deficiency in antigen-specific CD4+ T-cell-expressed IFN-γ led to a higher susceptibility to mucosal and gut-derived systemic OVA-C. rodentium infection. These results show that the IFN-γ produced by antigen-specific CD4+ T cells plays an important role in the defense against C. rodentium.

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Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

Science ◽

10.1126/science.aaz7548 ◽

2020 ◽

Vol 368 (6494) ◽

pp. eaaz7548 ◽

Cited By ~ 31

Author(s):

Zhiwei Zhou ◽

Huabin He ◽

Kun Wang ◽

Xuyan Shi ◽

Yupeng Wang ◽

...

Keyword(s):

Antitumor Immunity ◽

Interferon Γ ◽

Target Cells ◽

Cytotoxic Lymphocytes ◽

Cytotoxic Lymphocyte ◽

Granzyme A ◽

Tumor Clearance ◽

Ifn Γ ◽

Underlying Mechanisms ◽

Pore Forming Proteins

Cytotoxic lymphocyte–mediated immunity relies on granzymes. Granzymes are thought to kill target cells by inducing apoptosis, although the underlying mechanisms are not fully understood. Here, we report that natural killer cells and cytotoxic T lymphocytes kill gasdermin B (GSDMB)–positive cells through pyroptosis, a form of proinflammatory cell death executed by the gasdermin family of pore-forming proteins. Killing results from the cleavage of GSDMB by lymphocyte-derived granzyme A (GZMA), which unleashes its pore-forming activity. Interferon-γ (IFN-γ) up-regulates GSDMB expression and promotes pyroptosis. GSDMB is highly expressed in certain tissues, particularly digestive tract epithelia, including derived tumors. Introducing GZMA-cleavable GSDMB into mouse cancer cells promotes tumor clearance in mice. This study establishes gasdermin-mediated pyroptosis as a cytotoxic lymphocyte–killing mechanism, which may enhance antitumor immunity.

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Intraepithelial lymphocyte-derived interferon-γ evokes enterocyte apoptosis with parenteral nutrition in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00290.2002 ◽

2003 ◽

Vol 284 (4) ◽

pp. G629-G637 ◽

Cited By ~ 49

Author(s):

Hua Yang ◽

Yongyi Fan ◽

Daniel H. Teitelbaum

Keyword(s):

Parenteral Nutrition ◽

Fas Ligand ◽

Interferon Γ ◽

Intraepithelial Lymphocyte ◽

Wild Type ◽

Enterocyte Apoptosis ◽

Resultant Increase ◽

Ifn Γ ◽

Fas L ◽

Deficient Mice

Total parenteral nutrition (TPN) results in an increase in intraepithelial lymphocyte (IEL)-derived interferon-γ (IFN-γ) expression as well as an increase in epithelial cell (EC) apoptosis. This study examined the role that IEL-derived IFN-γ has in the increase in EC apoptosis. Mice received either TPN or oral feedings for 7 days. Small bowel EC apoptosis significantly rose in mice receiving TPN. The administration of TPN also significantly increased IEL-derived IFN-γ and Fas ligand (FasL) expression. EC apoptosis in IFN-γ knockout (IFNKO) mice that received TPN was significantly lower than in wild-type TPN mice. Sensitivity of EC to Fas-mediated apoptosis in IFNKO mice was significantly lower than in wild-type TPN mice. Apoptosis in Fas-deficient and FasL-deficient mice that received TPN was significantly lower than in wild-type mice that received TPN. The TPN-induced increase in IFN-γ expression appears to result in an increase in Fas-L expression and EC sensitivity to Fas, with a resultant increase in EC apoptosis. This may well be one of the mediators of increased EC apoptosis observed with TPN administration.

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Development of Prediction Models for New Integrated Models and a Bioscore System to Identify Bacterial Infections in Systemic Lupus Erythematosus

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.620372 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xvwen Zhai ◽

Min Feng ◽

Hui Guo ◽

Zhaojun Liang ◽

Yanlin Wang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Bacterial Infections ◽

Prediction Models ◽

Predictive Ability ◽

Treg Cells ◽

Interferon Γ ◽

Systemic Lupus ◽

Ifn Γ ◽

Factor Α

ObjectivesDistinguishing flares from bacterial infections in systemic lupus erythematosus (SLE) patients remains a challenge. This study aimed to build a model, using multiple blood cells and plasma indicators, to improve the identification of bacterial infections in SLE.DesignBuilding PLS-DA/OPLS-DA models and a bioscore system to distinguish bacterial infections from lupus flares in SLE.SettingDepartment of Rheumatology of the Second Hospital of Shanxi Medical University.ParticipantsSLE patients with flares (n = 142) or bacterial infections (n = 106) were recruited in this retrospective study.OutcomeThe peripheral blood of these patients was collected by the experimenter to measure the levels of routine examination indicators, immune cells, and cytokines. PLS-DA/OPLS-DA models and a bioscore system were established.ResultsBoth PLS-DA (R2Y = 0.953, Q2 = 0.931) and OPLS-DA (R2Y = 0.953, Q2 = 0.942) models could clearly identify bacterial infections in SLE. The white blood cell (WBC), neutrophile granulocyte (NEUT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), IL-10, interferon-γ (IFN-γ), and tumor necrosis factor α (TNF-α) levels were significantly higher in bacteria-infected patients, while regulatory T (Treg) cells obviously decreased. A multivariate analysis using the above 10 dichotomized indicators, based on the cut-off value of their respective ROC curve, was established to screen out the independent predictors and calculate their weights to build a bioscore system, which exhibited a strong diagnosis ability (AUC = 0.842, 95% CI 0.794–0.891). The bioscore system showed that 0 and 100% of SLE patients with scores of 0 and 8–10, respectively, were infected with bacteria. The higher the score, the greater the likelihood of bacterial infections in SLE.ConclusionsThe PLS-DA/OPLS-DA models, including the above biomarkers, showed a strong predictive ability for bacterial infections in SLE. Combining WBC, NEUT, CRP, PCT, IL-6, and IFN-γ in a bioscore system may result in faster prediction of bacterial infections in SLE and may guide toward a more appropriate, timely treatment for SLE.

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Update of a clinical prediction model for serious bacterial infections in preschool children by adding a host-protein-based assay: a diagnostic study

BMJ Paediatrics Open ◽

10.1136/bmjpo-2018-000416 ◽

2019 ◽

Vol 3 (1) ◽

pp. e000416

Author(s):

Chantal van Houten ◽

Josephine Sophia van de Maat ◽

Christiana Naaktgeboren ◽

Louis Bont ◽

R Oostenbrink

Keyword(s):

Prediction Model ◽

Bacterial Infections ◽

Viral Infections ◽

Interferon Γ ◽

Host Protein ◽

Diagnostic Study ◽

Double Blind ◽

C Statistic ◽

Serious Bacterial Infections ◽

Tract Infections

ObjectiveTo determine whether updating a diagnostic prediction model by adding a combination assay (tumour necrosis factor-related apoptosis-inducing ligand, interferon γ induced protein-10 and C reactive protein (CRP)) can accurately identify children with pneumonia or other serious bacterial infections (SBIs).DesignObservational double-blind diagnostic study.SettingTwo hospitals in Israel and four hospitals in the Netherlands.Patients591 children, aged 1–60 months, presenting with lower respiratory tract infections or fever without source. 96 of them had SBIs. The original Feverkidstool, a polytomous logistic regression model including clinical variables and CRP, was recalibrated and thereafter updated by using the assay.Main outcome measuresPneumonia, other SBIs or no SBI.ResultsThe recalibrated original Feverkidstool discriminated well between SBIs and viral infections, with a c-statistic for pneumonia of 0.84 (95% CI 0.77 to 0.92) and 0.82 (95% CI 0.77 to 0.86) for other SBIs. The discriminatory ability increased when CRP was replaced by the combination assay; c-statistic for pneumonia increased to 0.89 (95% CI 0.82 to 0.96) and for other SBIs to 0.91 (95% CI 0.87 to 0.94). This updated Feverkidstool improved diagnosis of SBIs mainly in children with low–moderate risk estimates of SBIs.ConclusionWe improved the diagnostic accuracy of the Feverkidstool by replacing CRP with a combination assay to predict pneumonia or other SBIs in febrile children. The updated Feverkidstool has the largest potential to rule out bacterial infections and thus to decrease unnecessary antibiotic prescription in children with low-to-moderate predicted risk of SBIs.

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Inhibition of Methylcholanthrene-induced Carcinogenesis by an Interferon γ Receptor–dependent Foreign Body Reaction

Journal of Experimental Medicine ◽

10.1084/jem.20011887 ◽

2002 ◽

Vol 195 (11) ◽

pp. 1479-1490 ◽

Cited By ~ 61

Author(s):

Zhihai Qin ◽

Hye-Jung Kim ◽

Jens Hemme ◽

Thomas Blankenstein

Keyword(s):

Dna Damage ◽

Foreign Body ◽

Host Defense ◽

Tissue Damage ◽

Defense Mechanisms ◽

Foreign Body Reaction ◽

Tumor Development ◽

Interferon Γ ◽

Ifn Γ ◽

Deficient Mice

The foreign body reaction is one of the oldest host defense mechanisms against tissue damage which involves inflammation, scarring, and encapsulation. The chemical carcinogen methylcholanthrene (MCA) induces fibrosarcoma and tissue damage in parallel at the injection site. Tumor development induced by MCA but not due to p53-deficiency is increased in interferon-γ receptor (IFN-γR)–deficient mice. In the absence of IFN-γR, MCA diffusion and DNA damage of surrounding cells is increased. Locally produced IFN-γ induces the formation of a fibrotic capsule. Encapsulated MCA can persist virtually life-long in mice without inducing tumors. Together, the foreign body reaction against MCA prevents malignant transformation, probably by reducing DNA damage. This mechanism is more efficient in the presence of IFN-γR. Our results indicates that inflammation and scarring, both suspected to contribute to malignancy, prevent cancer in certain situations.

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12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

Infection and Immunity ◽

10.1128/iai.00560-09 ◽

2009 ◽

Vol 77 (12) ◽

pp. 5690-5700 ◽

Cited By ~ 15

Author(s):

Melissa K. Middleton ◽

Alicia M. Zukas ◽

Tanya Rubinstein ◽

Michelle Kinder ◽

Emma H. Wilson ◽

...

Keyword(s):

Molecular Mechanisms ◽

Ex Vivo ◽

Acute Infection ◽

Chronic Phase ◽

Parasite Burden ◽

Brain Inflammation ◽

Interleukin 12 ◽

Unsaturated Lipids ◽

Ifn Γ ◽

Deficient Mice

ABSTRACT Interleukin-12 (IL-12) is critical for resistance to Toxoplasma gondii during both the acute and chronic stages of infection. However, the cellular and molecular pathways that regulate IL-12 production during chronic toxoplasmosis are incompletely defined. We recently discovered that 12/15-lipoxygenase (12/15-LOX), which oxidizes unsaturated lipids in macrophages, is a novel and selective regulator of IL-12 production. We now demonstrate the essential role of this enzyme in the chronic phase of toxoplasmosis. Although 12/15-LOX-deficient mice were resistant to acute T. gondii infection, 80% of 12/15-LOX-deficient mice died during chronic toxoplasmosis, compared to no deaths in wild-type controls. The morbidity of chronically infected 12/15-LOX mice was associated with an increase in brain inflammation and parasite burden. These data suggest that the evolution of the immune response to T. gondii is accompanied by an increasing requirement for 12/15-LOX-mediated signaling. Consistent with this conclusion, 12/15-LOX activity was enhanced during chronic, but not acute, toxoplasmosis. Furthermore, the enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis was associated with reduced production of IL-12 and gamma interferon (IFN-γ) that was not evident during acute infection. Importantly, ex vivo IFN-γ production by 12/15-LOX-deficient splenocytes could be rescued by the addition of recombinant IL-12. These data establish that 12/15-LOX is a critical mediator of the chronic type 1 inflammatory response and that immune mediators can be subject to distinct cellular and/or molecular mechanisms of regulation at different stages of inflammation.

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