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STAT1 employs myeloid cell-extrinsic mechanisms to regulate the neutrophil response and provide protection against invasive Klebsiella pneumoniae lung infection

ABSTRACT: STAT1 employs myeloid cell-extrinsic mechanisms to regulate the neutrophil response and provide protection against invasive Klebsiella pneumoniae lung infection

PROVIDER: PRJNA1055448 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27315300_1.fastq.gz	Fastqsanger.gz
	SRR27315300_2.fastq.gz	Fastqsanger.gz
	SRR27315293_1.fastq.gz	Fastqsanger.gz
	SRR27315293_2.fastq.gz	Fastqsanger.gz
	SRR27315294_1.fastq.gz	Fastqsanger.gz

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STAT1 employs myeloid cell-extrinsic mechanisms to regulate the neutrophil response and provide protection against invasive Klebsiella pneumoniae lung infection

Project description:Klebsiella pneumoniae (KP) are extracellular Gram-negative bacteria that cause infections in lower respiratory and urinary tract, and bloodstream. STAT1 is a master transcription factor that acts to maintain T-cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T-cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found STAT1-deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil-recruitment in the lung preceding widespread bacterial dissemination and lung injury development. Yet, myeloid cell STAT1 was dispensable for control of KP proliferation and dissemination, as myeloid cell-specific STAT1-deficient (LysMCre/WT;Stat1fl/fl) mice showed similar bacterial burden in lung, liver, and kidney as WT littermates. Surprisingly, IL-17 producing CD4+ T-cells infiltrated Stat1-/- mice lungs early during KP infection. Increase in Th17-cells in the lung was not due to preexisting immunity against KP and were consistent with circulating rather than tissue-resident CD4+ T-cells. However, blocking global IL17 signaling with anti-IL17-RC administration led to increased proliferation and dissemination of KP, suggesting IL17 provided by other innate immune cells is essential in defense against KP. Contrastingly, depletion of CD4+ T-cells reduced Stat1-/- mice lung bacterial burden indicating early CD4+ T-cell activation in the setting of global STAT1-deficiency is pathogenic. Altogether, our findings suggest STAT1 employs myeloid cell-extrinsic mechanisms to regulate neutrophil responses and provide protection against invasive KP by restricting non-specific CD4+ T-cell activation and immunopathology in the lung.

2024-01-10 | GSE251767 | GEO

STAT1 Employs Myeloid Cell-Extrinsic Mechanisms to Regulate the Neutrophil Response and Provide Protection against Invasive Klebsiella pneumoniae Lung Infection.

Project description:Klebsiella pneumoniae (KP) is an extracellular Gram-negative bacterium that causes infections in the lower respiratory and urinary tracts and the bloodstream. STAT1 is a master transcription factor that acts to maintain T cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found that STAT1 deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil recruitment in the lung preceding widespread bacterial dissemination and lung injury development. Yet, myeloid cell STAT1 was dispensable for control of KP proliferation and dissemination, because myeloid cell-specific STAT1-deficient (LysMCre/WT;Stat1fl/fl) mice showed bacterial burden in the lung, liver, and kidney similar to that of their wild-type littermates. Surprisingly, IL-17-producing CD4+ T cells infiltrated Stat1-/- murine lungs early during KP infection. The increase in Th17 cells in the lung was not due to preexisting immunity against KP and was consistent with circulating rather than tissue-resident CD4+ T cells. However, blocking global IL-17 signaling with anti-IL-17RC administration led to increased proliferation and dissemination of KP, suggesting that IL-17 provided by other innate immune cells is essential in defense against KP. Contrastingly, depletion of CD4+ T cells reduced Stat1-/- murine lung bacterial burden, indicating that early CD4+ T cell activation in the setting of global STAT1 deficiency is pathogenic. Altogether, our findings suggest that STAT1 employs myeloid cell-extrinsic mechanisms to regulate neutrophil responses and provides protection against invasive KP by restricting nonspecific CD4+ T cell activation and immunopathology in the lung.

| S-EPMC10832384 | biostudies-literature

Pancreatic Gene Expression from Wild-Type, Stat1-Transgenic, and Stat1-CC-Transgenic Mice

Project description:Pancreatic Gene Expression from Wild-Type, Stat1-Transgenic, and Stat1-CC-Transgenic Mice. This data was part of the set of data utilized to identify PARP9/DTX3L as a novel antiviral gene. Keywords: transgene state analysis RNA was extracted from the pancreas of 3 mice per genotype (wild-type, Stat1-Transgenic, Stat1-CC-Transgenic). Comparisons were made between Stat1-Transgenic and Stat1-CC-Transgenic mice.

2015-09-01 | E-GEOD-61414 | biostudies-arrayexpress

Tumor suppressor p53 employs RFX7 and ANKRA2

Project description:Tumor suppressor p53 employs RFX7 and ANKRA2

| PRJNA680800 | ENA

Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity

Project description:STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing Stat1-Y701F. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1-/- animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo suggesting a so-far unknown cytoplasmic function. Using immunofluorescence technology we uncovered the recruitment of STAT1 to the immunological synapse during NK cell killing. A Stat1ind mouse expressing FLAG-tagged STAT1α was used to study the STAT1α interactome in NK cells. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. We propose a novel function for STAT1 in the immunological synapse of NK cells regulating tumor surveillance and cytotoxicity.

2016-10-07 | PXD002206 | Pride

Comparison of pDCs isolated from recipients of STAT1+/+ vs. STAT1-/- bone marrow

Project description:The goal of this study is to determine if pDCs reconstituted from T cell depleted allogeneic STAT1-/- bone marrow express genes that contribute to Graft versus host disease (GVHD) resistance as compared to STAT1+/+ bone marrow Lethally irradiated B6 x C3H.SW mice were transplanted with T cell depleted 129 or 129 STAT1-/- bone marrow. 14 days later, pDCs were isolated from spleens by magnetic cell selection, and pooled from 12 mice/group. cDNA was generated and hybridized to an Affymetrix genechip mouse genome 430 2.0 array. Samples were normalized by RMA algorithm to a log2 intensity value and analyzed by Ingenuity Pathway Analysis v8.5 software.

2014-07-25 | E-GEOD-59731 | biostudies-arrayexpress

Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis

Project description:Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. The goal of this study was to investigate differences in gene expression in lesional skin from patients with mild extrinsic or intrinsic AD compared to skin from healthy controls and from lesional psoriasis skin. The aim was to identify differentially expressed genes involved in skin barrier formation and inflammation, and to compare our results with those reported for patients with moderate and severe AD. A total of 31 samples were analyzed: 8 healthy skin, 9 psoriatic plaques, 4 extrinsic AD lesional skin, 10 intrinsic AD lesional skin.

2016-03-08 | E-GEOD-75890 | biostudies-arrayexpress

Comparison of pDCs isolated from recipients of STAT1+/+ vs. STAT1-/- bone marrow

2014-07-25 | GSE59731 | GEO

hCAF1/CNOT7 regulates interferon signaling by targeting STAT1

Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape. mRNAs from cells expressing the siRNA siRNA duplexes targeting hCAF1, corresponding to the coding region 941-961 (kd) (hCAF1 NCBI Reference Sequence: NM_013354.5) and one non-targeting control siRNA (mock).

2013-12-31 | E-GEOD-43334 | biostudies-arrayexpress

Pancreatic Gene Expression from Wild-Type, Stat1-Transgenic, and Stat1-CC-Transgenic Mice

2015-09-01 | GSE61414 | GEO