In vivo role of platelets in bacterial blood infection

描述(由申请人提供)：众所周知，血小板在维持止血方面起着重要作用，但它们对其他过程的重要贡献正变得越来越明显。例如，血小板已被证明具有强大的杀菌活性，这表明在感染过程中具有重要的功能。同样，血流感染的患者通常会出现弥漫性血管内凝血等凝血疾病。最近，一种新的转基因小鼠品系已经被开发出来，它可以在不改变任何其他血液或免疫细胞亚型的情况下，在不同的时间内去除血小板。使用这只小鼠的初步结果表明，它们不能对血液感染金黄色葡萄球菌USA300产生有效的天然免疫反应，并在72小时内100%屈服于感染。而50%的野生型白纹伊蚊能在感染后存活20天以上。血小板耗尽的小鼠无法像野生型小鼠那样有效地清除血液中的细菌，并且在感染24小时后增加了肾脏中的细菌负担。这些观察背后的机制(S)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，将评估血小板增强中性粒细胞介导的宿主防御的能力，并确定与血小板增强的中性粒细胞活性有关的分子。最后，是血小板的杀伤力。将对金黄色葡萄球菌进行评估并阐明其分子机制(S)。在这项拨款申请中提出的实验将揭示血小板作为主要的天然免疫细胞的潜力，负责预防金黄色葡萄球菌的血液感染。重要的是要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)来对抗金黄色葡萄球菌感染。这项研究还优先考虑了血小板作为重要的先天性免疫细胞保护免受其他感染源(其他细菌、病毒、寄生虫)侵袭的潜力以及它们在保护免受感染方面的作用。

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.