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In vivo role of platelets in bacterial blood infection

血小板在细菌性血液感染中的体内作用

基本信息

批准号：
9231484
负责人：
Randall Glenn Worth
金额：
$ 37.88万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231484
关键词：
Abnormal Platelet Adenine Nucleotides Applications Grants Bacteria Bacterial Infections Biological Process Blood Blood Coagulation Disorders Blood Platelets Blood coagulation Cell Adhesion Molecules Cells Collagen Communicable Diseases Complement Receptor Data Defensins Diphtheria Toxin Disseminated Intravascular Coagulation Effector Cell Enterobacteria phage P1 Cre recombinase Exhibits Fibrinogen Flow Cytometry Genus staphylococcus Hemostatic function Host Defense Hour ITGAM gene Image Immune In Vitro Infection Infectious Agent Inflammation Inflammatory Innate Immune Response Interferons Interleukin-1 Kidney Kinetics Laboratories Length Lethal Dose 50 Leukocytes Mean Survival Times Measures Mediating Megakaryocytes Modeling Molecular Monitor Mouse Strains Mus Natural Immunity Neutrophil Activation Organ Organ Harvestings Oxygen P-selectin ligand protein Parasites Patients Physiological Platelet Factor 4 Play Pneumonia Prausnitz-Kustner Test Process Production Proteins RANTES Reporting Role Route SELP gene Sepsis Signal Transduction Skin Staining method Stains Staphylococcus aureus Stimulus Stroke TLR2 gene Testing Thrombin Thrombocytopenia Time Toll-like receptors Transgenic Mice Transient Ischemic Attack Virus Wild Type Mouse antimicrobial peptide atherogenesis bactericide base cell type combat cytokine diphtheria toxin receptor experimental study in vivo instrumentation killings microbial neutrophil new therapeutic target novel novel therapeutics nucleotide receptor pathogen promoter public health relevance receptor response scavenger receptor uptake

项目摘要

DESCRIPTION (provided by applicant): Platelets are known for their essential role in maintaining hemostasis but their important contributions to other processes are becoming more apparent. For example, platelets have been shown to have potent bactericidal activity suggesting an important function during infection. Similarly, patients with bloodstream infections typically present with coagulopathies such as disseminated intravascular coagulation. Recently, a new transgenic mouse strain has been developed that can be depleted of platelets for various lengths of time without altering any other blood or immune cell subtype. Preliminary results using this mouse show that they do not mount an effective innate immune response against blood infection with Staphylococcus aureusUSA300 and 100% succumb to the infection within 72 hrs. while >50% of their wild-type counterparts survive the infection for more than 20 days. Platelet-depleted mice are unable to clear the bacteria from blood as effectively as wild-type mice and have increased bacterial burden in kidneys 24 hours after infection. The mechanism(s) behind these observations will be determined through three aims. First, the kinetics of S. aureus clearance from blood will be determined and the important organs and specific cell types responsible for clearance will be identified. Secondly, the ability of platelet to enhance neutrophil-mediated host-defense will be evaluated and the molecules responsible for platelet-enhanced neutrophil activity will be determined. Lastly, the ability of platelets to kill . aureus will be assessed and the molecular mechanism(s) elucidated. The experiments proposed in this grant application will reveal the potential of platelets as major innate immune cells responsible for protection against S. aureus blood infection. It will be important to establih if platelets also combat S. aureus infection via more typical routes of entry (skin abrasions, pneumonia, etc.). This study also gives precedence to the potential of platelets being important innate immune cells protecting from other infectious agents (other bacteria, virus, parasites) as well as their role in protecting against infections.

描述（由申请方提供）：众所周知，血小板在维持止血方面发挥着重要作用，但其对其他过程的重要作用也越来越明显。例如，血小板已被证明具有有效的杀菌活性，表明在感染期间的重要功能。类似地，患有血流感染的患者通常表现为凝血病，例如弥散性血管内凝血。最近，已经开发出一种新的转基因小鼠品系，其可以在不同时间长度内耗尽血小板而不改变任何其他血液或免疫细胞亚型。使用该小鼠的初步结果显示，它们不产生针对金黄色葡萄球菌USA300血液感染的有效先天免疫应答，并且100%在72小时内死于感染。而>50%的野生型对应物在感染后存活超过20天。血小板耗尽的小鼠不能像野生型小鼠那样有效地清除血液中的细菌，并且在感染后24小时增加了肾脏中的细菌负荷。这些观察结果背后的机制将通过三个目标来确定。首先，研究了S.测定金黄色葡萄球菌从血液中的清除率，并鉴定负责清除的重要器官和特定细胞类型。其次，将评估血小板增强嗜中性粒细胞介导的宿主防御的能力，并确定负责血小板增强嗜中性粒细胞活性的分子。最后是血小板的杀伤能力。将评估金黄色葡萄球菌并阐明分子机制。在这项资助申请中提出的实验将揭示血小板作为主要的先天免疫细胞的潜力，负责保护免受S。金黄色葡萄球菌血液感染确定血小板是否也能对抗S.金黄色葡萄球菌感染通过更典型的途径进入（皮肤擦伤，肺炎等）。这项研究还优先考虑了血小板作为重要的先天免疫细胞保护免受其他感染因子（其他细菌，病毒，寄生虫）的潜力以及它们在保护免受感染方面的作用。