Statins as Inhibitors of Bacterial Host Cell Invasion

描述(申请人提供)：这项研究的长期目标是了解细菌宿主细胞在体外和体内入侵的分子机制。临床证据表明，在细菌性败血症之前，服用他汀类药物的患者预后有所改善。虽然其中一些有益的作用被归因于改善血流动力学或免疫调节，但我们最近发现，体外治疗浓度的辛伐他汀可以抑制金黄色葡萄球菌的宿主入侵，金黄色葡萄球菌是脓毒症最常见的病原体。抑制似乎主要是由于辛伐他汀耗尽了胆固醇生物合成途径中的异戊二烯中间体，而不是由于胆固醇本身的耗尽。辛伐他汀还导致与磷脂酰肌醇3-激酶(PI3K)调节亚基P85偶联的细胞内CDC42的积聚。提出的假设是，辛伐他汀部分地通过隔离胞浆中的PI3K亚型来抑制宿主的侵袭。拟议的研究将使用遗传方法将PI3K隔离在细胞质中，并评估宿主入侵是否减少。体内感染模型将被用来评估抑制宿主入侵是否增加了抗生素的疗效并防止了慢性、持续性感染，或者相反，辛伐他汀抑制非专业吞噬细胞的摄取是否损害了先天清除。总之，拟议的实验将解决他汀类药物作用中一种潜在的新机制，该机制可能导致更直接的治疗方法，以规避他汀类药物用作传染病辅助治疗的问题。被称为他汀类药物的降胆固醇药物有许多非降胆固醇的好处，包括降低因全身感染而死亡的风险。这项拟议的工作将让本科生和硕士研究生参与他汀类药物的保护作用的调查，追求他汀类药物是否能阻止感染的问题，总体目标是开发用于治疗传染病的辅助疗法。与公共健康相关：被称为他汀类的降胆固醇药物具有许多非降胆固醇的好处，包括降低因全身感染而死亡的风险。这项拟议的工作将让本科生和硕士研究生参与他汀类药物的保护作用的调查，追求他汀类药物是否能阻止感染的问题，总体目标是开发用于治疗传染病的辅助疗法。

DESCRIPTION (provided by applicant): The long-term objective of this research is to understand the molecular mechanisms of bacterial host cell invasion both in vitro and in vivo. Clinical evidence indicates improved prognosis for patients on a statin regimen prior to bacterial sepsis. While some of these beneficial effects have been attributed to improved hemodynamics or immunomodulation, we have recently found that therapeutic concentrations of simvastatin in vitro inhibits host invasion by Staphylococcus aureus, the most common etiologic agent in sepsis. Inhibition appears to be due primarily to the depletion of isoprenoid intermediates by simvastatin within the cholesterol biosynthesis pathway rather than to the depletion of cholesterol itself. Simvastatin also led to the cytosolic accumulation of CDC42 coupled to the phosphoinositide 3-kinase (PI3K) regulatory subunit p85. The proposed hypothesis is that simvastatin inhibits host invasion in part through sequestration of PI3K isoforms within the cytosol. Proposed studies will use genetic approaches to sequester PI3K within the cytosol and assess whether host invasion is decreased. In vivo models of infection will be used to assess whether the inhibition of host invasion increases antibiotic efficacy and prevents chronic, persistent infection, or conversely, whether simvastatin inhibition of uptake by non-professional phagocytes impairs innate clearance. Together, the proposed experiments will address a potentially novel mechanism in the action of statins that could lead to more directed therapeutics to circumvent issues in statin use as an adjunct therapy for infectious disease. The cholesterol-lowering drugs known as statins have a number of non-cholesterol lowering benefits, including a decreased risk of death due to systemic infection. This proposed work will engage undergraduate and master's level students in the investigation of the protective effect of statins, pursuing the question of whether statins block infection, with an overall goal of developing adjunctive therapies for the treatment of infectious disease. PUBLIC HEALTH RELEVANCE: The cholesterol-lowering drugs known as statins have a number of non-cholesterol lowering benefits, including a decreased risk of death due to systemic infection. This proposed work will engage undergraduate and master's level students in the investigation of the protective effect of statins, pursuing the question of whether statins block infection, with an overall goal of developing adjunctive therapies for the treatment of infectious disease.