Mechanisms of type I IFN enhanced gonococcal infection

I型干扰素增强淋球菌感染的机制

• 批准号: 9979327
• 负责人: Douglas T Golenbock
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979327
• 关键词: Antibiotic Resistance; Antibiotics; Bacteria; Bacterial DNA; Bacterial Infections; Bacterial Sexually Transmitted Diseases; Binding; Cells; Cephalosporins; Cyclic GMP; Cytokine Gene; Cytosol; DNA; DNA Binding; Data; Development; Disease; Drug-resistant Neisseria Gonorrhoeae; Ectopic Pregnancy; Environment; Enzymes; Estrogens; Female; Gene Activation; Gene Expression; Genetic Transcription; Goals; Gonadal Steroid Hormones; Gonorrhea; Gram-Negative Bacteria; Growth; HIV; Hormones; Host Defense; Human; IFNAR1 gene; IRF3 gene; Immune; Immune Evasion; Immune signaling; Immunologic Receptors; In Vitro; Individual; Infection; Infertility; Inflammation; Innate Immune System; Interferon Receptor; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Knockout Mice; Lead; Link; Liquid Chromatography; Mediating; Membrane; Methods; Modeling; Molecular; Mus; Myeloid Cells; Neisseria gonorrhoeae; Neutrophil Infiltration; Nucleotides; Pathology; Pathway interactions; Pelvic Inflammatory Disease; Periodicity; Phagocytes; Phosphorylation; Play; Predisposition; Production; Proteins; Public Health; Receptor Gene; Reporting; Role; Second Messenger Systems; Sexual Transmission; Sexually Transmitted Diseases; Signal Pathway; Signal Transduction; Source; Stimulator of Interferon Genes; TANK-binding kinase 1; TLR4 gene; Therapeutic; Therapeutic Intervention; Time; Tissues; Transfection; Treatment Efficacy; Vagina; Vesicle; Virus; Woman; Work; base; chronic pelvic pain; in vivo; infection burden; lipooligosaccharide; men; mouse model; novel; novel strategies; prevent; receptor; recruit; reproductive tract; response; tandem mass spectrometry; transmission process; vaginal infection

Project Abstract Infection with Neisseria gonorrhoeae (Ng) remains a major public health issue. Ng gonococci are sexually transmitted between individuals causing inflammation and pelvic inflammatory disease (PID). The emergence of antibiotic-resistant Ng is cause for concern, and Ng strains with antibiotic-resistance to nearly all of the approved therapeutics have developed with cephalosporins being the last remaining effective antibiotic. Understanding the mechanisms that underlie Ng susceptibility will be crucial for the development of new and effective therapeutic options for treating gonococcal disease. We discovered that Ng bacteria trigger innate cytokine gene expression through two separate pathways, the Toll-like receptor 4 (TLR4) pathway and via a recently discovered intracellular DNA sensing pathway. DNA released into the cytosol during infection or introduced by transfection binds to an enzyme cyclic-GMP-AMP synthase (cGAS). DNA-activated cGAS produces a cyclic di-nucleotide (cdN), 2’3’-cGAMP, which acts as a second messenger and triggers a protein stimulator of interferon genes (STING). STING, in turn, activates TANK-binding kinase 1 (TBK-1) leading to interferon regulatory factor 3 (IRF3) activation and type I interferon (IFN) gene expression. Bacteria cdNs can also activate STING and type I IFN expression, another example of immune evasion. Based on our preliminary studies, where we found that type I IFNs greatly enhanced gonococcal infection, we hypothesize that Ng-induced type I IFN is a method of immune evasion that enhances the replication and survival of Ng in host phagocytes. Recently, an estrogen-induced type I IFN (IFN-epsilon) was identified in mice and humans. IFN-epsilon is expressed in the genital tract of both men and women and binds the same receptor as other type I IFNs. Estrogen is also known to promote gonococcal infection of vaginal tissues in humans and in mouse models of Ng infection. The goal of this project is to assess the role of estrogen-induced and immune receptor-induced type I IFN in enhancing Ng infection. We will identify and characterize the molecular pathways that are responsible for controlling Ng infection. In Aim 1, we will!elucidate the role of type I IFNs in enhancing Ng infection. These studies will be performed using several knockout mouse models that our labs have generated and examine the role of type I IFN receptor (IFNAR) signaling in promoting Ng infection. In Aim 2, we will look at the molecular mechanism(s) of immune receptor-driven type I IFN production, particularly the cGAS and STING receptor pathways and the role of outer membrane vesicles, during Ng infection. The goal of these studies is to develop novel strategies for therapeutic interventions that may ameliorate or prevent the damaging sequelae of Ng infection and PID.

项目摘要 淋病奈瑟菌 (Ng) 感染仍然是一个重大的公共卫生问题。 Ng 淋球菌有性行为 在引起炎症和盆腔炎（PID）的个体之间传播。的出现 抗生素耐药性 Ng 值得关注，Ng 菌株对几乎所有已批准的抗生素都具有耐药性 治疗方法已发展到头孢菌素是最后剩下的有效抗生素。理解 Ng 易感性背后的机制对于开发新的有效药物至关重要 治疗淋球菌疾病的治疗选择。 我们发现 Ng 细菌通过两个不同的途径触发先天细胞因子基因表达，即 Toll 样受体 4 (TLR4) 途径和最近发现的细胞内 DNA 传感途径。脱氧核糖核酸 在感染过程中释放到胞质溶胶中或通过转染引入与环-GMP-AMP 酶结合 合酶（cGAS）。 DNA 激活的 cGAS 产生环状二核苷酸 (cdN)、2’3’-cGAMP，它充当 第二信使并触发干扰素基因的蛋白质刺激物（STING）。 STING 反过来激活 TANK 结合激酶 1 (TBK-1) 导致干扰素调节因子 3 (IRF3) 激活和 I 型干扰素 (干扰素)基因表达。细菌 cdN 还可以激活 STING 和 I 型 IFN 表达，这是另一个例子 免疫逃避。根据我们的初步研究，我们发现 I 型干扰素大大增强了 对于淋球菌感染，我们假设 Ng 诱导的 I 型 IFN 是一种免疫逃避方法，可增强 Ng 在宿主吞噬细胞中的复制和存活。 最近，在小鼠和人类体内发现了雌激素诱导的 I 型干扰素（IFN-ε）。 IFN-ε是 在男性和女性的生殖道中表达，并与其他 I 型干扰素结合相同的受体。雌激素 已知它还能促进人和 Ng 感染小鼠模型中阴道组织的淋球菌感染。 该项目的目标是评估雌激素诱导和免疫受体诱导的 I 型干扰素在 增强Ng感染。我们将识别并表征负责的分子途径 控制 Ng 感染。在目标1中，我们将阐明I型IFN在增强Ng感染中的作用。这些研究 将使用我们实验室生成的几种基因敲除小鼠模型进行，并检查 I 型干扰素受体 (IFNAR) 信号传导促进 Ng 感染。在目标 2 中，我们将研究分子 免疫受体驱动的 I 型 IFN 产生机制，特别是 cGAS 和 STING 受体 Ng 感染期间外膜囊泡的途径和作用。这些研究的目标是开发 治疗干预的新策略可以改善或预防 Ng 的破坏性后遗症 感染和 PID。