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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（由申请方提供）：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。S.金黄色葡萄球菌限制了可用抗生素治疗的有效性。该项目的长期目标是确定新的方法，可用于降低严重程度和改善葡萄球菌感染的结果。葡萄球菌成孔毒素，如α-毒素和Panton-Valentine杀白细胞素，通过触发促炎介质的释放和诱导易感细胞的死亡而促成葡萄球菌感染的发病机制。在我们之前的研究中，我们发现I型干扰素（IFN-α和IFN-β）有效地降低葡萄球菌α毒素引发的促炎反应和细胞死亡。我们的初步数据还表明，I型干扰素通过诱导α-毒素孔的形成，α-毒素孔是一种干扰素刺激的基因，参与质膜脂质周转。基于这些新的发现，我们假设I型干扰素诱导的α-毒素保护作用在葡萄球菌感染过程中对宿主有益。为了验证这一假设，我们计划确定I型干扰素诱导的α毒素保护是否降低了葡萄球菌感染的严重程度并改善了葡萄球菌感染的结局（目的1）。我们将评估I型干扰素对细菌清除，组织损伤和诱导促炎细胞因子（IL-1-β，IL-6，TNF-α）和趋化因子（MIP-2和KC）在实验性葡萄球菌感染的小鼠模型。此外，我们建议确定PLSCR 1的作用，作为最有前途的候选基因，在干扰素诱导的保护α毒素（目的2）。使用RNA干扰方法和PLSCR 1敲除小鼠，我们将确定PLSCR 1是否是必要的和/或足够的I型干扰素诱导的保护免受α毒素。这些实验将为I型干扰素在调节宿主与沙门氏菌相互作用中的作用提供新的机制见解。金黄色。这些研究的结果也应该帮助我们评估是否靶向I型干扰素或PLSCR 1具有治疗葡萄球菌感染的治疗潜力。公共卫生相关性：S.金黄色葡萄球菌感染限制了用于治疗葡萄球菌感染的可用抗生素疗法的有效性，在美国，葡萄球菌感染与每年约12，000例患者死亡有关。我们发现I型干扰素限制了由α毒素（沙门氏菌的主要毒力因子）引发的炎症反应和细胞死亡。金黄色。我们建议评估干扰素诱导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。