Targeting the Host Adenosine A2A Receptor to Protect Against Fatal Rickettsiosis Using an Approved Parkinson's Disease Drug

使用经批准的帕金森病药物靶向宿主腺苷 A2A 受体来预防致命的立克次体病

• 批准号: 9510124
• 负责人: Bin Gong
• 金额: $ 24.53万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-08 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9510124
• 关键词: ADORA2A gene; Adenylate Cyclase; Adherence; Adhesions; Anatomy; Antibiotic Therapy; Arthropods; Atomic Force Microscopy; Bacteria; Bacterial Adhesins; Bacterial Adhesion; Binding; Biochemical; Biomechanics; Bioterrorism; Cell model; Cell surface; Clinical Trials; Coupling; Cyclic AMP; Data; Disease; Dose; Early Diagnosis; Endothelial Cells; Endothelium; Epidemic; Evaluation; Experimental Designs; Functional Imaging; Human; In Vitro; Infection; Inhalation; Maps; Measures; Methods; Microvascular Permeability; Modeling; Molecular; Mus; Outcome; Parkinson Disease; Pathology; Pharmaceutical Preparations; Play; Proteins; Reporting; Rickettsia; Rickettsia Infections; Rocky Mountain Spotted Fever; Role; Signal Pathway; Signal Transduction; Surface; System; Techniques; Testing; Therapeutic; Typhus; Vaccines; Vascular Endothelial Cell; base; experimental study; human disease; in vivo; insight; molecular recognition; nano; nanomechanical; nanomechanics; novel; prophylactic; protective efficacy; receptor; receptor binding

PROJECT SUMMARY/ ABSTRACT Rickettsioses represent devastating human infections. Epidemic typhus and Rocky Mountain spotted fever (RMSF) are two of the most lethal infections known to humans. Although rickettsial infections can be controlled by appropriate broad-spectrum antibiotic therapy if diagnosed early, up to 20% of misdiagnosed or untreated and 5% of treated RMSF cases can be fatal. In addition, high infectivity and severe illness after inhalation make rickettsiae potential bioterrorism threats. Disseminated endothelial infection and endothelial barrier disruption with increased microvascular permeability are the central pathophysiologic features. However, a vaccine is not available for fatal rickettsioses, and novel host mechanism-based prophylactics and therapeutics are urgently needed. We have reported that cyclic adenosine monophosphate (cAMP) signaling plays a critical role during fatal rickettsioses through the cAMP-exchange protein directly activated by cAMP (Epac) signaling axis. However, the role of upstream signaling pathway in this pathology is completely unknown. Adenosine A2A receptor (A2AR) is predominantly expressed in vascular endothelial cells (ECs). A2AR has been well recognized to serve as an upstream regulator of cAMP signaling and to be able to stimulate the intracellular cAMP accumulation. We found that the approved Parkinson’s disease (PD) drug KW6002, an A2AR antagonist, dramatically suppressed rickettsial infection in both a cell model and a vasculature model. Inactivation of A2AR by KW6002 weakens the nano-binding force of the rickettsial adhesin rOmpB to living endothelial cells (ECs), thereby limiting rickettsial adherence to ECs. These findings suggest that the A2AR- cAMP signaling pathway may control rickettsial infection by acting on host rickettsial-binding receptor(s) in ECs. We propose our central hypothesis that the selective A2AR antagonist KW6002 can provide protective efficacy against rickettsial infection by impeding bacterial adhesion to ECs. To test this hypothesis, we will pursue the following Specific Aims: Aim 1: To identify endothelial surface targets regulated by A2AR during rickettsial adhesion. Aim 2: To define the nanomechanical mechanism of rickettsial adhesion to endothelial surfaces regulated by A2AR. Aim 3: To evaluate whether KW6002 can protect against lethal rickettsial infection by arresting rickettsial adherence to the endothelial lining in vivo. We will test our hypothesis by employing cutting-edge approaches, i.e., 1) functional imaging of the interactions between rickettsial adhesins and living EC surfaces using AFM, and 2) a novel, anatomy-based, in vivo quantitative bacterial adhesion measuring system. Outcomes will provide deeper insights into the biomechanical and molecular mechanisms of rickettsial infections, but more importantly it is expected that the data will support the scientific justification for repurposing an approved drug for immediate use in clinical trials to battle the dreadful human diseases caused by Rickettsia.

项目摘要/摘要 立克sios代表毁灭性的人类感染。流行病和落基山斑点发烧 （RMSF）是人类已知的两种最致命的感染。虽然可以控制立克感染 通过适当的广谱抗生素疗法，如果提早诊断出，多达20％的诊断或未经治疗 5％的RMSF病例可能是致命的。此外，受伤后高感染和严重疾病 使人力体的潜在生物恐怖主义威胁。传播内皮感染和内皮屏障 微血管通透性增加的破坏是中央病理生理特征。但是， 疫苗不可用于致命的立克斯和基于新型宿主机制的预防和​​治疗 迫切需要。我们报告说，环状腺苷单磷酸（CAMP）信号传导起着关键 通过cAMP（EPAC）信号直接激活的cAMP交换蛋白在致命的立克表现中的作用 轴。但是，上游信号通路在该病理学中的作用是完全未知的。腺苷 A2A受体（A2AR）主要在血管内皮细胞（ECS）中表达。 A2AR很好 公认是cAMP信号传导的上游调节器，并能够刺激细胞内 营地积累。我们发现已批准的帕金森氏病（PD）药物KW6002，A2AR 在细胞模型和脉管系统模型中，对抗者，极大地抑制了立克感染。 KW6002对A2AR的灭活削弱了立克蛋白rompb的纳米结合力 内皮细胞（EC），从而限制了立克对EC的依从性。这些发现表明A2AR- 营地信号通路可以通过在宿主立人内存结合受体上作用，可以控制身心感染。 ECS。我们提出了我们的中心假设，即选择性A2AR拮抗剂KW6002可以提供受保护 通过阻碍细菌对EC的粘附，对立克感染的功效。为了检验这一假设，我们将 追求以下具体目的：目标1：确定由A2AR调节的内皮表面目标 立克粘附。目的2：定义立克粘附的纳米力学机制以对内皮的内皮 由A2AR调节的表面。目标3：评估KW6002是否可以预防致命的立克 通过逮捕体内内皮内皮衬里的粘附来感染。我们将通过 采用尖端方法，即1）立克蛋白之间相互作用的功能成像 使用AFM和2）一种新型的基于解剖的，体内定量细菌粘附的EC表面 测量系统。结果将为生物力学和分子机制提供更深入的见解 人力学感染，但更重要的是，预计数据将支持科学依据 为了重新利用经批准的药物，以立即用于临床试验，以与可怕的人类疾病作斗争 人力车引起。