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

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对美国的医疗保健造成了惊人的负担。金黄色葡萄球菌日益增加的抗生素耐药性限制了现有抗生素治疗的有效性。该项目的长期目标是确定可用于降低葡萄球菌感染严重程度和改善结果的新方法。葡萄球菌的成孔毒素，如α -毒素和潘通-瓦伦丁白细胞杀死素，通过触发促炎介质的释放和诱导易感细胞死亡，有助于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）能有效降低葡萄球菌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 -毒素孔的形成来阻止α -毒素孔的形成，α -毒素孔是一种干扰素刺激的基因，参与质膜脂的转换。基于这些新发现，我们假设I型干扰素诱导的对α毒素的保护在葡萄球菌感染期间有利于宿主。为了验证这一假设，我们计划确定I型干扰素诱导的对α毒素的保护是否会降低葡萄球菌感染的严重程度并改善结果（目的1）。我们将在实验性葡萄球菌感染小鼠模型中评估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）的影响。此外，我们建议确定PLSCR1作为最有希望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干扰方法和PLSCR1敲除小鼠，我们将确定PLSCR1对于I型干扰素诱导的α -毒素保护是否必要和/或充分。这些实验应该为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提供新的机制见解。这些研究的结果也应该有助于我们评估靶向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：金黄色葡萄球菌抗生素耐药性的增加限制了现有抗生素治疗葡萄球菌感染的有效性，葡萄球菌感染与美国每年约12,000名患者死亡有关。我们发现I型干扰素限制由α -毒素（金黄色葡萄球菌的主要毒力因子）引发的炎症反应和细胞死亡。我们建议评估干扰素诱导的对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。

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.