Statins as Inhibitors of Bacterial Host Cell Invasion

描述（由申请人提供）：本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，他汀类药物治疗可改善患者预后。虽然其中一些有益作用归因于血液动力学或免疫调节的改善，但我们最近发现，体外治疗浓度的辛伐他汀可抑制金黄色葡萄球菌（脓毒症最常见的病因）对宿主的侵袭。抑制作用似乎主要是由于辛伐他汀在胆固醇生物合成途径中消耗了类异戊二烯中间体，而不是胆固醇本身的消耗。辛伐他汀还导致CDC42与磷酸肌醇3-激酶（PI3K）调控亚基p85偶联的细胞质积累。提出的假设是辛伐他汀部分通过隔离细胞质内的PI3K异构体抑制宿主入侵。拟议的研究将使用遗传方法将PI3K隔离在细胞质内，并评估宿主入侵是否减少。体内感染模型将用于评估抑制宿主入侵是否会提高抗生素疗效并预防慢性、持续性感染，或者相反，辛伐他汀对非专业吞噬细胞摄取的抑制是否会损害先天清除。总之，拟议的实验将解决他汀类药物作用的潜在新机制，这可能导致更有针对性的治疗方法，以避免他汀类药物作为感染性疾病辅助治疗的问题。被称为他汀类的降胆固醇药物有许多非降胆固醇的益处，包括降低因全身感染而死亡的风险。这项拟议的工作将吸引本科生和硕士水平的学生调查他汀类药物的保护作用，追求他汀类药物是否阻断感染的问题，以开发感染性疾病治疗的辅助疗法为总体目标。公共卫生相关性：他汀类降胆固醇药物有许多非降胆固醇的益处，包括降低因全身感染而死亡的风险。这项拟议的工作将吸引本科生和硕士水平的学生调查他汀类药物的保护作用，追求他汀类药物是否阻断感染的问题，以开发感染性疾病治疗的辅助疗法为总体目标。

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.