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）感染仍然是一个主要的公共卫生问题。淋球菌在性方面 在个体之间传播，引起炎症和盆腔炎（PID）。的出现 耐药的Ng引起了人们的关注，Ng菌株对几乎所有批准的药物都具有耐药性。 已经开发了头孢菌素作为最后剩余的有效抗生素的治疗方法。理解 Ng易感性的基础机制对于开发新的有效的 治疗淋球菌疾病的治疗选择。 我们发现，Ng细菌通过两种不同的途径触发先天性细胞因子基因表达， Toll样受体4（TLR 4）途径和最近发现的细胞内DNA传感途径。DNA 在感染过程中释放到胞质溶胶中或通过转染引入， 合成酶（cGAS）。DNA活化的cGAS产生环状二核苷酸（cdN），2 '3'-cGAMP，其充当DNA活化剂。 第二信使和触发干扰素基因（STING）的蛋白质刺激物。STING反过来激活 TANK结合激酶1（TBK-1）导致干扰素调节因子3（IRF 3）活化和I型干扰素 (IFN)基因表达。细菌cdN还可以激活STING和I型IFN表达，这是细菌cdN的另一个实例。 免疫逃避基于我们的初步研究，我们发现I型干扰素大大增强了 淋球菌感染，我们假设，Ng-induced I型IFN是一种免疫逃避的方法，增强 Ng在宿主吞噬细胞中的复制和存活。 最近，雌激素诱导的I型IFN（IFN-γ）在小鼠和人中被鉴定。IFN-epsilon是 在男性和女性的生殖道中表达，并与其他I型IFN结合相同的受体。雌激素 还已知在人和Ng感染的小鼠模型中促进阴道组织的淋球菌感染。 本项目的目的是评估雌激素诱导和免疫受体诱导的I型IFN在 增强Ng感染。我们将识别和表征负责 控制Ng感染。目标1，我们会的！阐明I型IFN在增强Ng感染中的作用。这些研究 将使用我们的实验室已经产生的几种敲除小鼠模型进行，并检查 I型IFN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产生的机制，特别是cGAS和STING受体 途径和外膜囊泡的作用，在Ng感染。这些研究的目的是发展 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。