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:
- 金额:$ 46.69万
- 依托单位:
- 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:
- 关键词:AcuteAerosolsAnimalsAntibiotic TherapyApoptosisBacteriaBacterial InfectionsBiological ModelsBioterrorismCASP8 geneCaspaseCategoriesCattleCell Surface ReceptorsCellsCenters for Disease Control and Prevention (U.S.)Chlamydia InfectionsChlamydia trachomatisCoxiellaCoxiella burnetiiDataDevelopmentDinucleoside PhosphatesDiseaseDisease OutbreaksDrosophila genusDrosophila melanogasterEpidemiologyGenesGenomeGoalsGoatGram-Negative BacteriaGrowthHealthHumanImmune responseImmunityIndividualInfectionInflammasomeInflammatoryInfluenzaInhalationInnate Immune ResponseInsectaInterferon Type IInvertebratesLife Cycle StagesMediatingMedicalMetabolismMethodsMicrobial BiofilmsModelingMolecularNational Institute of Allergy and Infectious DiseaseNatural ImmunityOrthologous GenePathogenesisPathogenicityPeriodicityPhasePlayProcessPublishingQ FeverReceptor ActivationResearchRiskRoleRouteSecond Messenger SystemsSheepSignal TransductionStimulator of Interferon GenesSymptomsTestingTherapeuticTicksUnited StatesVaccinesVector-transmitted infectious diseaseVertebratesWorkZoonosesantimicrobialbiodefensecell motilitychronic infectioncytokinegenetic signaturehost colonizationhuman pathogeninsightinvertebrate hostmacrophagenovelnovel therapeutic interventionnovel therapeuticspathogenphosphoric diester hydrolasepreventpriority pathogensensortranscription factortransmission processvector
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.
项目概要/摘要:
环状二核苷酸(Cyclic dinucleotides,CDN)在革兰氏阴性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,例如运动性、生物膜形成、宿主
定植、细菌生长和代谢。CDN水平由细菌编码的
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
在感染过程中,CDN可以提醒先天免疫反应。一种主要的细胞溶质传感器,
在动物宿主中的胞内CDN是STING,其在其激活时触发先天免疫应答
通过诱导I型干扰素和促炎细胞因子。因此,合成CDN已经被
在感染前外源性应用,以刺激炎性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,治疗衣原体感染的反应。
另一种革兰氏阴性、专性细胞内嗜巨噬细胞细菌是贝氏柯克斯体,
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,柯克斯体也在蜱虫中发现,它们被认为是媒介。急性期
这种疾病在人类中的主要特征是流感样症状,
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,
需要开发目前的抗生素治疗以减少感染动物中的柯克斯体负荷。我们的初步
数据表明,CDN在Coxiella感染期间产生,并且Coxiella基因组含有
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,
关于CDN如何在Coxiella感染期间引发STING介导的宿主反应。因此,我们建议
确定CDN如何控制对贝氏柯克斯体感染的先天免疫反应。在目标1中,我们
在脊椎动物和无脊椎动物模型中表征STING介导的宿主对柯克斯体感染的反应。在
目的2,我们将从caspase激活的角度来剖析STING在柯克斯体感染中的作用机制
和程序性细胞死亡在目标3中,我们将用CDN刺激宿主的先天免疫应答,
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,拟议的工作将表征CDN介导的先天免疫反应,以柯克斯体
感染和我们如何利用CDN来减少整体Coxiella负担。使用无脊椎动物模型
柯克斯体感染可能适用于其他媒介传播疾病。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的CDN/STING介导的免疫机制,
适用于其他病原性感染。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Alan Gabriel Goodman其他文献
Alan Gabriel Goodman的其他文献
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{{ truncateString('Alan Gabriel Goodman', 18)}}的其他基金
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
- 批准号:
9981625 - 财政年份:2019
- 资助金额:
$ 46.69万 - 项目类别:
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氏柯克斯体感染的负担
- 批准号:
9816592 - 财政年份:2019
- 资助金额:
$ 46.69万 - 项目类别:
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
- 批准号:
10669187 - 财政年份:2019
- 资助金额:
$ 46.69万 - 项目类别:
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氏柯克斯体感染的负担
- 批准号:
10197797 - 财政年份:2019
- 资助金额:
$ 46.69万 - 项目类别:
Identifying host genetic determinants of Coxiella burnetii pathogenesis
鉴定伯氏柯克斯体发病机制的宿主遗传决定因素
- 批准号:
9387775 - 财政年份:2017
- 资助金额:
$ 46.69万 - 项目类别:
Conserved Immune Response to Sensing Cytosolic DNA
对感测胞质 DNA 的保守免疫反应
- 批准号:
8889860 - 财政年份:2014
- 资助金额:
$ 46.69万 - 项目类别:
Conserved Immune Response to Sensing Cytosolic DNA
对感测胞质 DNA 的保守免疫反应
- 批准号:
8900923 - 财政年份:2014
- 资助金额:
$ 46.69万 - 项目类别:
Conserved Immune Response to Sensing Cytosolic DNA
对感测胞质 DNA 的保守免疫反应
- 批准号:
8567657 - 财政年份:2013
- 资助金额:
$ 46.69万 - 项目类别:
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