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发挥重要的第二信使作用，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、细菌生长和新陈代谢。 CDN 水平受到细菌编码的严格控制二鸟苷酸/二腺苷酸环化酶和磷酸二酯酶。除了调节细菌的生命周期 CDN 可以在感染期间提醒先天免疫反应。主要的细胞质传感器动物宿主的细胞内 CDN 是 STING，一旦激活，就会触发先天免疫反应通过诱导 I 型干扰素和促炎细胞因子。因此，合成 CDN 已在感染前外源性应用，以刺激炎症小体活性并减少衣原体负荷沙眼衣原体，一种革兰氏阴性、专性细胞内细菌。因此 CDN 可用于启动免疫除了标准的两周抗生素治疗外，对衣原体感染的治疗反应。另一种革兰氏阴性、专性细胞内巨噬细胞嗜性细菌是伯内氏柯克斯体 (Coxiella burnetii)，它是人畜共患病Q热的病原体。柯克斯体传播的主要途径是通过气溶胶。然而，蜱虫中也发现了柯克斯体，它们被认为是媒介。急性期人类疾病的主要特征是流感样症状，并且出现流感样症状的个体慢性感染必须接受18-24个月的抗生素治疗。我们认为替代方法目前需要开发抗生素治疗方法来减少受感染动物的柯克斯体负荷。我们的初步数据表明 CDN 是在柯克斯体感染期间产生的，并且柯克斯体基因组包含编码二鸟苷酸/二腺苷酸环化酶和磷酸二酯酶的推定基因。然而，鲜为人知关于 CDN 在 Coxiella 感染期间如何引发 STING 介导的宿主反应。因此，我们建议确定 CDN 如何控制对伯内特柯克斯体感染的先天免疫反应。在目标 1 中，我们将表征脊椎动物和无脊椎动物模型中 STING 介导的宿主对柯克斯体感染的反应。在目标 2，我们将剖析 STING 在 Coxiella 感染过程中有关 caspase 激活的作用机制和程序性细胞死亡。在目标 3 中，我们将用 CDN 刺激宿主先天免疫反应脊椎动物和无脊椎动物模型，以减少柯克斯体感染的程度。总之，拟议的工作将描述 CDN 介导的对 Coxiella 的先天免疫反应感染以及我们如何利用 CDN 来减少总体柯克斯体负担。无脊椎动物模型的应用柯克斯体感染可能适用于其他媒介传播的疾病。本研究中获得的信息将对先天免疫有广泛的影响，有助于开发治疗柯克斯体的新疗法感染，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。