Mechanisms of type I IFN enhanced gonococcal infection

I型干扰素增强淋球菌感染的机制

基本信息

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
项目类别：
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

项目摘要

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。在引起炎症和盆腔炎（PID）的个体之间传播。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经发展起来，头孢菌素是最后剩下的有效抗生素。 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。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 DNA 激活的 cGAS 产生环状二核苷酸 (cdN) 2'3'-cGAMP，其作用为第二信使并触发干扰素基因的蛋白质刺激物（STING），进而激活。 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 (IFN) 基因表达也可以激活 STING 和 I 型 IFN 表达，这是另一个例子。根据我们的初步研究，我们发现 I 型干扰素大大增强了免疫逃避。淋球菌感染，我们追查Ng诱导的I型干扰素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)。在男性和女性的生殖道中表达，并与其他 I 型雌激素结合相同的受体。还已知会促进人类和 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 型干扰素在我们将识别并描述导致 Ng 感染的分子途径。在目标 1 中，我们将阐明 I 型干扰素在增强 Ng 感染中的作用。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，我们将研究分子机制。免疫受体驱动的 I 型 IFN 产生机制，特别是 cGAS 和 STING 受体这些研究的目标是开发 Ng 感染过程中的途径和外膜囊泡的作用。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。