Type I interferon-induced protection from staphylococcal pore-forming toxins

I 型干扰素诱导的针对葡萄球菌成孔毒素的保护

基本信息

批准号：
7842612
负责人：
TIMUR OLEGOVICH YAROVINSKY
金额：
$ 24.83万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7842612
关键词：
Adherence Antibiotic Resistance Antibiotic Therapy Apoptotic Bacterial Infections CXC Chemokines Candidate Disease Gene Cell Death Cell membrane Cells Cessation of life Data Effectiveness Epithelial Cells Genes Goals Healthcare Immune Infection Inflammation Mediators Inflammatory Inflammatory Response Injury Inpatients Interferon Type I Interferon-alpha Interferon-beta Interferons Interleukin-1 beta Interleukin-6 Knockout Mice Life Link Lipids Lung Membrane Lipids Mononuclear Morbidity - disease rate Mus Outcome Panton-Valentine leukocidin Pathogenesis Patients Phagocytes Phosphatidylserines Phospholipids Potassium RNA Interference Regulation Research Role Severities Staphylococcal Infections Staphylococcal Protein A Staphylococcus alpha toxin Staphylococcus aureus Testing Therapeutic Tissues Toxin Tumor Necrosis Factor-alpha United States Virulence Virulence Factors alpha Toxin cytokine design human TNF protein improved in vivo Model insight mortality mouse model novel novel strategies overexpression pathogen phospholipid scramblase prevent public health relevance research study response type I interferon receptor

项目摘要

DESCRIPTION (provided by applicant): Morbidity and mortality associated with severe infections caused by Staphylococcus aureus present a staggering burden on the healthcare in the United States. The increasing antibiotic resistance of S. aureus limits effectiveness of available antibiotic therapies. The long-term goal of this project is to identify novel approaches that could be used to decrease severity and improve the outcome of staphylococcal infections. Staphylococcal pore-forming toxins, such as alpha-toxin and Panton-Valentine leukocidin, contribute to the pathogenesis of staphylococcal infections by triggering the release of pro-inflammatory mediators and inducing death in susceptible cells. During our prior studies we found that type I interferons (IFN-alpha and IFN-beta) potently decrease pro-inflammatory responses and cell death triggered by staphylococcal alpha-toxin. Our preliminary data also suggest that type I interferons prevent formation of alpha-toxin pores via induction of), an interferon-stimulated gene involved in plasma membrane lipid turnover. Building on these novel findings, we hypothesize that type I interferon-induced protection from alpha-toxin benefits the host during staphylococcal infections. To test this hypothesis, we plan to determine whether type I interferon-induced protection from alpha-toxin decreases severity and improves the outcome of staphylococcal infection (Aim 1). We will evaluate the effects of type I interferons on bacterial clearance, tissue injury and induction of pro-inflammatory cytokines (IL-1-beta, IL-6, TNF-alpha) and chemokines (MIP-2 and KC) during experimental staphylococcal infection in a mouse model. Furthermore, we propose to determine the role of PLSCR1, as the most promising candidate gene, in interferon-induced protection from alpha-toxin (Aim 2). Using RNA-interference approach and PLSCR1-knockout mice, we will determine whether PLSCR1 is necessary and/or sufficient for type I interferon-induced protection from alpha-toxin. These experiments should provide novel mechanistic insights into the roles of type I interferons in the regulation of host interactions with S. aureus. The results of these studies should also help us to evaluate whether targeting type I interferons or PLSCR1 has a therapeutic potential for treatment of staphylococcal infections. PUBLIC HEALTH RELEVANCE: The increasing antibiotic resistance of S. aureus limits effectiveness of available antibiotic therapies for treatment of staphylococcal infections, which are linked to approximately 12,000 patient deaths per year in the United States. We found that type I interferons limit inflammatory responses and cell death triggered by alpha-toxin, a major virulence factor of S. aureus. We propose to evaluate whether interferon-induced protection from alpha-toxin benefits the host and has a therapeutic potential for treatment of staphylococcal infections.

描述（由申请人提供）：与金黄色葡萄球菌引起的严重感染相关的发病率和死亡率给美国的医疗保健带来了惊人的负担。金黄色葡萄球菌的抗生素耐药性的增加限制了可用的抗生素疗法的有效性。该项目的长期目标是确定可用于降低严重程度并改善葡萄球菌感染结果的新型方法。葡萄球菌孔形成的毒素，例如α-毒素和Panton-Valentine白细胞素，通过触发促炎性介体的释放并诱导易感细胞中的死亡来促进葡萄球菌感染的发病机理。在我们先前的研究中，我们发现I型干扰素（IFN-Alpha和IFN-BETA）有效地降低了促炎反应和由葡萄球菌α-毒素触发的细胞死亡。我们的初步数据还表明，I型干扰素可以通过诱导来防止α-毒素孔形成），这是一种参与质膜脂质周转的干扰素刺激的基因。在这些新颖的发现的基础上，我们假设I型干扰素诱导的保护免受α-毒素的保护在葡萄球菌感染过程中受益于宿主。为了检验这一假设，我们计划确定I型干扰素诱导的α-毒素的保护是否会降低严重程度并改善葡萄球菌感染的结果（AIM 1）。我们将评估I型干扰素对细菌清除，组织损伤的影响，并诱导促炎性细胞因子（IL-1-β，IL-6，TNF-Alpha）和趋化因子（MIP-2和KC）在实验性葡萄球菌感染过程中的影响。此外，我们建议确定PLSCR1作为最有前途的候选基因在干扰素诱导的α-毒素保护中的作用（AIM 2）。使用RNA解关方法和PLSCR1敲除小鼠，我们将确定PLSCR1是否需要和/或足以用于I型干扰素诱导的α-毒素的保护。这些实验应提供有关I型干扰素在调节宿主与金黄色葡萄球菌相互作用中的作用的新型机械见解。这些研究的结果还应帮助我们评估靶向I型干扰素或PLSCR1是否具有治疗葡萄球菌感染的治疗潜力。公共卫生相关性：金黄色葡萄球菌的抗生素耐药性增加限制了可用的抗生素疗法对葡萄球菌感染的治疗的有效性，这与美国每年约12,000例患者死亡有关。我们发现I型干扰素限制了α-毒素触发的炎症反应和细胞死亡，α-毒素是金黄色葡萄球菌的主要毒力因子。我们建议评估干扰素诱导的免受α-毒素的保护是否有益于宿主，并具有治疗葡萄球菌感染的治疗潜力。