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

• 批准号: 8838860
• 负责人: Randall Glenn Worth
• 金额: $ 37.31万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838860
• 关键词: 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; Exhibits; Fibrinogen; Flow Cytometry; Genus staphylococcus; Health; Hemostatic function; Host Defense; Hour; ITGAM gene; Image; Immune; Immune response; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Interferons; Interleukin-1; Kidney; Kinetics; Laboratories; Length; Lethal Dose 50; Leukocytes; Life; 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; Process; Production; Proteins; RANTES; Reporting; Role; Route; SELP gene; Sepsis; Signal Transduction; Skin; Staining method; Stains; Staphylococcus aureus; Stimulus; Stroke; Testing; Thrombin; Thrombocytopenia; Time; Toll-Like Receptor 2; Toll-like receptors; Transgenic Mice; Transient Ischemic Attack; Virus; Wild Type Mouse; antimicrobial peptide; atherogenesis; bactericide; base; cell type; combat; cytokine; diphtheria toxin receptor; in vivo; instrumentation; killings; microbial; neutrophil; new therapeutic target; novel; novel therapeutics; nucleotide receptor; pathogen; platelet typing; promoter; receptor; recombinase; research study; response; scavenger receptor; uptake

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（由申请人提供）：血小板以其维持止血的重要作用而闻名，但其对其他过程的重要贡献越来越明显。例如，血小板已被证明具有强大的杀菌活性，表明其在感染期间具有重要功能。同样，血液感染患者通常表现为凝血功能障碍，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，可以在不改变任何其他血液或免疫细胞亚型的情况下在不同时间内耗尽血小板。使用该小鼠的初步结果表明，它们不能对金黄色葡萄球菌usa300的血液感染产生有效的先天免疫反应，并且在72小时内100%死亡。而50%的野生型病毒在感染后存活超过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小时肾脏中的细菌负担增加。这些观察结果背后的机制将通过三个目标来确定。首先，将确定金黄色葡萄球菌从血液中清除的动力学，并确定负责清除的重要器官和特定细胞类型。其次，血小板增强中性粒细胞介导的宿主防御的能力将被评估，负责血小板增强中性粒细胞活性的分子将被确定。最后，血小板的杀伤能力。金黄色葡萄球菌将被评估和分子机制(s)阐明。在这项拨款申请中提出的实验将揭示血小板作为主要先天免疫细胞的潜力，负责保护人体免受金黄色葡萄球菌血液感染。确定血小板是否也通过更典型的进入途径（皮肤擦伤、肺炎等）对抗金黄色葡萄球菌感染将是很重要的。这项研究还优先考虑了血小板作为重要的先天免疫细胞的潜力，它可以保护我们免受其他感染因子（其他细菌、病毒、寄生虫）的侵害，也可以保护我们免受感染。