Exploiting a cyclic dinucleotide-mediated immune response to reduce the burden of Coxiella burnetii infection

利用环状二核苷酸介导的免疫反应来减轻伯内氏立克次体感染的负担

基本信息

批准号：
10406352
负责人：
Alan Gabriel Goodman
金额：
$ 46.69万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-23 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406352
关键词：
Acute Aerosols Animals Antibiotic Therapy Apoptosis Bacteria Bacterial Infections Biological Models Bioterrorism CASP8 gene Caspase Categories Cattle Cell Surface Receptors Cells Centers for Disease Control and Prevention (U.S.)Chlamydia Infections Chlamydia trachomatis Coxiella Coxiella burnetii Data Development Dinucleoside Phosphates Disease Disease Outbreaks Drosophila genus Drosophila melanogaster Epidemiology Genes Genome Goals Goat Gram-Negative Bacteria Growth Health Human Immune response Immunity Individual Infection Inflammasome Inflammatory Influenza Inhalation Innate Immune Response Insecta Interferon Type I Invertebrates Life Cycle Stages Mediating Medical Metabolism Methods Microbial Biofilms Modeling Molecular National Institute of Allergy and Infectious Disease Natural Immunity Orthologous Gene Pathogenesis Pathogenicity Periodicity Phase Play Process Publishing Q Fever Receptor Activation Research Risk Role Route Second Messenger Systems Sheep Signal Transduction Stimulator of Interferon Genes Symptoms Testing Therapeutic Ticks United States Vaccines Vector-transmitted infectious disease Vertebrates Work Zoonoses antimicrobial biodefense cell motility chronic infection cytokine genetic signature host colonization human pathogen insight invertebrate host macrophage novel novel therapeutic intervention novel therapeutics pathogen phosphoric diester hydrolase prevent priority pathogen sensor transcription factor transmission process vector

项目摘要

Project Summary/Abstract: Cyclic dinucleotides (CDNs) play important second messenger roles in Gram-negative bacteria, regulating a number of different types of bacterial processes such as motility, biofilm formation, host colonization, bacterial growth, and metabolism. CDNs levels are tightly controlled by bacterial encoded diguanylate/diadenylate cyclases and phosphodiesterases. In addition to regulating bacterial life cycle processes, CDNs can alert the innate immune response during infection. A major cytosolic sensor for intracellular CDNs in animal hosts is STING, which upon its activation, triggers an innate immune response through the induction of type I interferon and pro-inflammatory cytokines. As such, synthetic CDNs have been applied exogenously prior to infection to stimulate inflammasome activity and reduce the load of Chlamydia trachomatis, a Gram-negative, obligate intracellular bacterium. Thus CDNs can be used to initiate an immune response to therapeutically treat Chlamydia infection, in addition to standard two-week antibiotic therapy. Another Gram-negative, obligate intracellular, macrophage-tropic bacterium is Coxiella burnetii, which is the causative agent of the zoonotic disease Q fever. The primary route of Coxiella transmission is through aerosols. However, Coxiella is also found in ticks, and they have been implicated as vectors. Acute phase of the disease in humans is characterized primarily by influenza-like symptoms, and individuals that develop chronic infection must undergo 18-24 months of antibiotic therapy. We contend that alternative methods to current antibiotic treatments need to be developed to reduce Coxiella load in infected animals. Our preliminary data suggests that CDNs are produced during Coxiella infection and that the Coxiella genome contains putative genes that encode diguanylate/diadenylate cyclases and phosphodiesterases. However, little is known about how CDNs elicit a STING-mediated host response during Coxiella infection. Thus, we propose to determine how CDNs control the innate immune response to Coxiella burnetii infection. In Aim 1, we will characterize the STING-mediated host response to Coxiella infection in vertebrate and invertebrate models. In Aim 2, we will dissect STING's mechanism of action during Coxiella infection with regard to caspase activation and programmed cell death. In Aim 3, we will stimulate the host innate immune response with CDNs in vertebrate and invertebrate models to reduce the magnitude of Coxiella infection. Together, the proposed work will characterize the CDN-mediated innate immune response to Coxiella infection and how we can exploit CDNs to reduce overall Coxiella burden. The use of invertebrate models of Coxiella infection may be applicable to other vector-borne diseases. The information gained in this study will have broad-ranging impacts in innate immunity towards to the development of new therapies to treat Coxiella infection, and we will identify potentially novel CDN/STING-mediated mechanisms of immunity that will be applicable to other pathogenic infections.

项目摘要/摘要：环状二核苷酸（CDN）在革兰氏阴性细菌中扮演重要的第二使者角色，调节许多不同类型的细菌过程，例如运动，生物膜形成，宿主定植，细菌生长和代谢。 CDNS水平由细菌编码紧密控制二甘氨酸/二丁二基酸酸环化酶和磷酸二酯酶。除了调节细菌生命周期过程，CDN可以在感染过程中提醒先天免疫反应。一个主要的胞质传感器动物宿主中的细胞内CDN刺是刺激性的，它激活后会触发先天的免疫反应通过诱导I型干扰素和促炎细胞因子。因此，合成CDN已经在感染前外源应用以刺激炎性体活性并减少衣原体的负荷沙眼，一种革兰氏阴性，可强制性细胞内细菌。因此，CDN可用于启动免疫除了标准的两周抗生素治疗外，对治疗治疗的反应治疗治疗。另一个革兰氏阴性的细胞内，巨噬细胞 - 热带细菌是Coxiella burnetii，它是人畜共患病Q发烧的病因。考克斯传输的主要途径是通过气溶胶。但是，coxiella也被发现在tick中，并且被认为是向量。急性相人类中的疾病主要由类似流感的症状和发展的个体来表征慢性感染必须接受18-24个月的抗生素治疗。我们认为这种替代方法需要开发当前的抗生素治疗，以减少感染动物的coxiella载荷。我们的初步数据表明，CDN是在Coxiella感染过程中产生的，Coxiella基因组包含编码二烷基化/二二二甲基酸环化酶和磷酸二酯酶的假定基因。但是，鲜为人知关于CDN如何在考克斯菌感染期间引起刺激介导的宿主反应。因此，我们建议确定CDN如何控制对Coxiella burnetii感染的先天免疫反应。在AIM 1中，我们将表征了脊椎动物和无脊椎动物模型中刺激介导的宿主对Coxiella感染的反应。在 AIM 2，我们将在Coxiella感染过程中剖析Sting在Caspase激活中的作用机理和程序性细胞死亡。在AIM 3中，我们将刺激宿主与CDN的先天免疫反应脊椎动物和无脊椎动物模型，以减少考克斯菌感染的幅度。拟议的工作将共同表征CDN介导的先天免疫对Coxiella 感染以及我们如何利用CDN来减轻总体coxiella负担。使用无脊椎动物模型考克斯菌感染可能适用于其他载体传播疾病。这项研究中获得的信息将对天生的免疫力产生广泛的影响，以开发新疗法以治疗考克斯氏菌感染，我们将确定潜在的新型CDN/STING介导的免疫机制适用于其他病原感染。