Neisseria gonorrhoeae exploits host interferon epsilon to establish infection in the female urogenital tract

淋病奈瑟菌利用宿主干扰素ε在女性泌尿生殖道中建立感染

基本信息

批准号：
10317367
负责人：
Douglas T Golenbock
金额：
$ 81.3万
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：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317367
关键词：
Affect Anti-Bacterial Agents Antibiotics Antimicrobial Cationic Peptides Antiviral Agents Attenuated Bacteria Bacterial Adhesion Bacterial Infections Bacterial Sexually Transmitted Diseases Cells Cervical Complement Cytidine Monophosphate N-Acetylneuraminic Acid Cytometry Data Dichloromethylene Diphosphonate Drug-resistant Neisseria Gonorrhoeae Ectopic Pregnancy Effector Cell Environment Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Estrogen Therapy Estrogens Female Female genitalia Gene Expression Genes Gonadal Steroid Hormones Gram-Negative Bacteria HIV Hormones Host Defense Human Immune Immune Evasion Immune system Incidence Infection Infertility Inflammation Innate Immune Response Interferon-alpha Interferons Knock-out Knockout Mice Lead Leukocytes Lipid A Lipopolysaccharides Mediating Menstrual cycle Metabolism Molecular Monoclonal Antibodies Mus Myeloid Cells Neisseria gonorrhoeae Nucleic Acids Pathway interactions Pattern Pelvic Inflammatory Disease Phagocytes Phase Phenotype Play Predisposition Production Proteins Proteomics Public Health Receptor Signaling Recombinants Regulation Resistance Role Sexual Transmission Sexually Transmitted Diseases Sialic Acids Sialyltransferases Signal Transduction Tissues Vagina Viral Proteins Wild Type Mouse Woman antimicrobial bactericide cathelicidin antimicrobial peptide cell type chemokine chronic pelvic pain cytokine efflux pump enhancing factor human model in vivo knockout animal lipooligosaccharide mouse model neutralizing monoclonal antibodies pathogenic bacteria phosphoethanolamine prevent receptor recruit reproductive tract response sialic acid binding Ig-like lectin sialylation transcriptome sequencing transmission process type I interferon receptor urogenital tract virtual

项目摘要

PROJECT ABSTRACT Neisseria gonorrhoeae (Ng) is a sexually-transmitted gram-negative bacterium that causes inflammation and pelvic inflammatory disease (PID). In the U.S., the incidence of Ng is rising dramatically. Alarmingly, Ng has become increasingly resistant to all approved antibiotics. Interferon-epsilon (IFN-e) is a type I IFN that is highly expressed by epithelial cells of the female urogenital tract (both in mice and humans) but not in leukocytes. IFN-e, unlike the other type I IFNs, is not induced by bacterial “pathogen-associated molecular patterns,” such as lipopolysaccharides (LPS) or nucleic acids. Rather, IFN-e is regulated by sex hormones in the urogenital tract. We discovered that estrogen contributes to Ng infection by inducing the expression of IFN-e. Estrogen treatment dramatically prolongs Ng infection of the female genital tract. Type I IFNs, including IFN-e, share a common receptor, the IFN-alpha/beta receptor (IFNAR). Our data using IFNAR and IFN-e knockout (KO) animals, as well as blocking mAbs to IFNAR, strongly support the hypothesis that estrogen-induced type I IFNs contribute to Ng immune evasion. In the absence of IFNAR signaling, Ng is virtually incapable of maintaining colonization of the female urogenital tract. Furthermore, local administration of recombinant IFN-e (rIFN-e) protein completely reverted the phenotype to resemble the wild- type mice. Preliminary studies suggest that this may be related to regulation of cationic antimicrobial peptides (CAMP), such as CRAMP, as well as the sialylation of Ng lipooligosaccharide (LOS). We hypothesize that estrogen-induced IFN-e is required for productive Ng infection because it regulates the availability of sialic acid precursors to Ng sialyltransferase, thus, allowing Ng to evade AMP killing. In Aim 1, we will assess the impact of estrogen and IFN-e on gene expression in epithelial cells in the female genital tract during infection using both mouse and human models of Ng infection. We will use proteomics and gene expression approaches to determine if IFN-e regulates the expression of CAMPs and complement proteins in the genital tract. In Aim 2, we will determine how IFNAR-expressing cell types promote Ng survival. We will also assess the impact of type I IFN on the intrinsic bactericidal activity of phagocytes and their recruitment to the genital tract. In Aim 3, we will assess the impact of IFN-e on Ng genes, particularly genes that regulate CAMP evasion, and their impact on killing of Ng in the absence of IFN-e. We will also determine if IFN-e reduces the sensitivity of Ng to complement and/or CRAMP-mediated killing by regulating LOS sialyation. The ability to modulate IFN responses during sexually-transmitted infections is a valid and potentially transformative strategy to ameliorate or prevent the damaging sequelae of Ng infection and PID.

项目摘要淋病奈瑟菌 (Ng) 是一种性传播的革兰氏阴性细菌，可引起炎症和在美国，盆腔炎（PID）的发病率正在急剧上升。对所有批准的抗生素的耐药性越来越强。干扰素-ε (IFN-e) 是一种 I 型干扰素，在女性泌尿生殖道上皮细胞中高度表达（在小鼠和人类中）但在白细胞中则不然与其他 I 型 IFN 不同，IFN-e 不是由细菌诱导的。 “病原体相关分子模式”，例如脂多糖（LPS）或核酸，而 IFN-e 是。受泌尿生殖道性激素的调节我们发现雌激素通过以下方式促进 Ng 感染。诱导 IFN-e 表达的治疗可显着延长女性生殖器的 Ng 感染时间。 I 型 IFN，包括 IFN-e，共享一个共同的受体，即 IFN-α/β 受体 (IFNAR)。使用 IFNAR 和 IFN-e 敲除 (KO) 动物，以及阻断 IFNAR 的单克隆抗体，强烈支持假设雌激素诱导的 I 型 IFN 在缺乏 IFNAR 的情况下有助于 Ng 免疫逃避。此外，Ng 几乎无法维持女性泌尿生殖道的局部定植。重组干扰素-e (rIFN-e) 蛋白的施用完全恢复了与野生型相似的表型。初步研究表明，这可能与阳离子抗菌肽的调节有关。 (CAMP)，例如 CRAMP，以及 Ng 脂寡糖 (LOS) 的唾液酸化。雌激素诱导的 IFN-e 是生产性 Ng 感染所必需的，因为它调节唾液酸的可用性 Ng 唾液酸转移酶的前体，因此允许 Ng 逃避 AMP 杀伤。在目标 1 中，我们将评估雌激素和 IFN-e 对女性上皮细胞基因表达的影响我们将使用蛋白质组学和人类 Ng 感染模型来研究感染期间的生殖道。基因表达方法以确定 IFN-e 是否调节 CAMP 和补体蛋白的表达在目标 2 中，我们将确定表达 IFNAR 的细胞类型如何促进 Ng 存活。还评估了 I 型干扰素对吞噬细胞内在杀菌活性及其募集的影响在目标 3 中，我们将评估 IFN-e 对 Ng 基因的影响，特别是调节基因。 CAMP 逃避，以及在没有 IFN-e 的情况下它们对杀死 Ng 的影响我们还将确定 IFN-e 是否会减少。 Ng 通过调节 LOS 唾液酸化对补体和/或 CRAMP 介导的杀伤的敏感性。在性传播感染期间调节干扰素反应的能力是有效且潜在的改善或预防 Ng 感染和 PID 造成的破坏性后遗症的变革性策略。