Epithelial type I interferon signaling in Salmonella typhimurium infection

鼠伤寒沙门氏菌感染中上皮 I 型干扰素信号传导

• 批准号: 9506338
• 负责人: Cagla Tukel
• 金额: $ 23.78万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9506338
• 关键词: Ablation; Acute; Address; Animals; Bacterial Infections; Binding; Caspase; Cell Death; Cell Nucleus; Complex; Cytokine Receptors; Cytokine Signaling; Data; Defect; Defense Mechanisms; Development; Enteral; Environment; Epithelial; Epithelial Cells; Equilibrium; Exhibits; Gastroenteritis; Genes; Genetic; Genetic Transcription; Homo; Host Defense; IFNAR1 gene; Immune response; Immune system; Immunologics; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Interferon Type I; Interferon-alpha; Interferons; Intestines; Invaded; Janus kinase; Knowledge; Microbe; Mus; Neutrophil Infiltration; Nitrates; Pathway interactions; Phosphorylation; Population; Positioning Attribute; Proteins; Receptor Signaling; Role; STAT protein; STAT1 gene; STAT2 gene; Salmonella; Salmonella enterica; Salmonella infections; Salmonella typhimurium; Serotyping; Signal Transduction; Testing; United States; Vacuole; Wild Type Mouse; base; commensal microbes; cytokine; defense response; enteric pathogen; foodborne; gut microbiota; in vitro Assay; innovation; intestinal epithelium; microbial community; microbiota; microorganism; mutant; neutrophil; pathogen; public health relevance; receptor; receptor binding; transcription factor

SUMMARY Cytokines are key mediators of inflammation and the host immune response. For many cytokines, signaling cascades are initiated by the binding of cytokines to their cognate receptor and the phosphorylation of Signal Transducers and Activators of Transcription (STAT) proteins by receptor bound Janus kinases (JAK). STAT proteins then form homo or heterodimer complexes, which translocate to the nucleus and regulate the transcription of multiple genes. Despite the high number of cytokines, there are only seven different STAT proteins that determine the fate of cytokine receptor signaling. Type I IFN signaling cascades begin following the binding of IFN/ to their cognate receptor (IFNAR). IFNAR activation leads to the formation of STAT1/STAT1 homodimers and STAT1/STAT2 heterodimers that each trigger distinct signaling cascades. Animals deficient in STAT1 signaling or IFNAR exhibit defects in inflammasome formation, caspase activation, and inflammatory cell death during infection with S. Typhimurium. However, it remains unclear whether genetic ablation of STAT1/STAT2 signaling alone changes the host response to Salmonella infection. The objectives of this application are to determine the mechanisms by which STAT2 dependent type I interferon signaling in epithelial cells contributes to intestinal inflammation that enables S. Typhimurium to outgrow the microbiota. Our central hypothesis that STAT2-dependent type I IFN signaling in epithelial cells leads to neutrophil recruitment, which in turn creates a microaerophilic and nitrate-rich environment enabling the luminal outgrowth of S. Typhimurium.

总结 细胞因子是炎症和宿主免疫应答的关键介质。对于许多 细胞因子，信号级联是由细胞因子与其同源受体的结合引发的 以及信号转导和转录激活因子（STAT）蛋白的磷酸化， 受体结合Janus激酶（JAK）。STAT蛋白然后形成同源或异源二聚体复合物， 转移到细胞核并调节多个基因的转录。尽管高 在许多细胞因子中，只有七种不同的STAT蛋白决定了细胞因子的命运。 细胞因子受体信号传导。I型IFN信号传导级联开始于IFN γ/IFN β与 其同源受体（IFNAR）。IFNAR激活导致STAT 1/STAT 1的形成 同源二聚体和STAT 1/STAT 2异源二聚体，其各自触发不同的信号传导级联。 STAT 1信号传导或IFNAR缺陷的动物表现出炎性小体形成的缺陷， 半胱天冬酶激活和炎性细胞死亡。鼠伤寒。但 目前尚不清楚单独基因切除STAT 1/STAT 2信号传导是否会改变宿主 对沙门氏菌感染的反应。本申请的目的是确定 上皮细胞中STAT 2依赖性I型干扰素信号传导的机制 肠道炎症使S.使鼠伤寒杆菌的数量超过微生物的数量。我们的中央 上皮细胞中STAT 2依赖性I型IFN信号转导导致中性粒细胞 招聘，这反过来又创造了一个微需氧和硝酸盐丰富的环境，使 腔生长S.鼠伤寒。