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.

摘要 细胞因子是炎症和宿主免疫反应的关键介质。对许多人来说 细胞因子，信号级联是由细胞因子与其同源受体结合而启动的 以及信号转导和转录激活因子(STAT)蛋白的磷酸化 受体结合的Janus激酶(JAK)。STAT蛋白然后形成同源或异源二聚体复合体， 它们转位到细胞核，调节多个基因的转录。尽管有很高的 细胞因子的数量，只有七种不同的STAT蛋白决定了 细胞因子受体信号转导。I型干扰素信号级联在干扰素/与 它们的同源受体(IFNAR)。IFNAR激活导致STAT1/STAT1的形成 同源二聚体和STAT1/STAT2异源二聚体各自触发不同的信号级联。 缺乏STAT1信号或IFNAR的动物表现出炎性小体形成的缺陷， 鼠伤寒沙门氏菌感染过程中caspase的激活和炎性细胞的死亡。然而，它 目前尚不清楚单独基因消融STAT1/STAT2信号是否会改变宿主 对沙门氏菌感染的反应。此应用程序的目标是确定 上皮细胞中STAT2依赖的I型干扰素信号参与的机制 使鼠伤寒沙门氏菌生长超过微生物区系的肠道炎症。我们的中央 上皮细胞中依赖STAT2的I型干扰素信号导致中性粒细胞的假说 招募，这反过来又创造了一个微好氧和富含硝酸盐的环境，使 鼠伤寒沙门氏菌的管腔生长。