Adaptation of Staphylococcus aureus to Mn-limitation imposed by the host

金黄色葡萄球菌对宿主施加的锰限制的适应

基本信息

批准号：
8316652
负责人：
Thomas Everett Kehl-Fie
金额：
$ 5.39万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316652
关键词：
Ablation Abscess Address Antibiotic Resistance Antibiotics Antioxidants Bacteria Bacterial Genes Bacterial Infections Bacterial Model Cessation of life Color Communities Coupled Development Disease Electrophoresis Environment Growth Hospitals Host Defense Human body Image Immunity In Vitro Infection Kinetics Laboratories Lasers Leukocyte L1 Antigen Complex Manganese Mass Spectrum Analysis Mediating Medical Metals Modeling Monitor Morbidity - disease rate Mus Nutrient Nutritional Oxidative Stress Plasma Process Proteins Proteomics Regulon Repression Resistance development S100A8 gene S100A9 gene Site Staphylococcal Infections Staphylococcus aureus Starvation System Techniques Tissues Vertebrates Virulence Work bacteria infection mechanism burden of illness combat experience in vivo manganese deficiency meetings methicillin resistant Staphylococcus aureus mortality mutant neutrophil new therapeutic target novel therapeutic intervention novel therapeutics pathogen prevent research study resistance mechanism

项目摘要

DESCRIPTION (provided by candidate): Bacterial infections are of substantial global concern due to increasing antibiotic resistance. Staphylococcus aureus is a pathogen of alarm because of the ability of the bacterium to infect nearly every site in the human body. This adaptability combined with increasing antibiotic resistance results in the high levels of morbidity and mortality associated with staphylococcal infections. A powerful strategy utilized by vertebrates to combat bacterial pathogens is the sequestration of essential nutrients, a process known as nutritional immunity. Recent work found that during invasive staphylococcal disease mature abscesses are virtually devoid of manganese (Mn). Further work revealed that the sequestration of Mn during staphylococcal infection is dependent on the neutrophil protein calprotectin (CP) a heterodimer of S100A8 and S100A9. In a murine model of infection, CP-deficient mice have increased staphylococcal burdens, suggesting that S. aureus is Mn starved during infection. This idea is further supported by the observation that during infection Mn-dependent bacterial processes are inhibited. In total, these results suggest that CP causes S. aureus to become Mn starved during infection and that this starvation is critical to host defense. Even though vertebrates create an environment virtually devoid of Mn, S. aureus remains capable of causing significant and devastating disease. These observations led us to hypothesize that S. aureus must somehow adapt to the Mn limitation imposed by the host. S. aureus is known to express dedicated Mn transporters, which may help this pathogen resist the effects of vertebrate metal sequestration. However, the increased staphylococcal virulence in CP-deficient mice suggests that expression of Mn transporters by S. aureus is not sufficient to prevent metal starvation. Although it is known that vertebrates sequester Mn, the kinetics of this process have not been elucidated and the extent of Mn starvation imposed on S. aureus remain unknown. Furthermore, how S. aureus adapts to Mn starvation imposed by CP also remains unclear. This application proposes to determine when during infection the host sequesters Mn and the level of metal starvation that is experienced by S. aureus. Additionally, the proposed experiments will determine the contribution of dedicated Mn import systems to resisting CP and elucidate how S. aureus adapts to Mn starvation. The Specific Aims of this application are as follows: Aim 1. Evaluate the kinetics of Mn sequestration during infection and the extent of Mn deficiency experienced by S. aureus. Aim 2. Determine if Mn import systems contribute to the ability of S. aureus to overcome vertebrate Mn sequestration. Aim 3. Determine how S. aureus adapts to Mn limitation imposed by the host. PUBLIC HEALTH RELEVANCE: Bacterial pathogens, such as Staphylococcus aureus, are of serious concern due to their substantial disease burden and increasing antibiotic resistance. To combat these invaders, vertebrates limit the availability of essential nutrients. These studies wil determine the processes that S. aureus uses to overcome the nutrient limiting environment created by the host, facilitating the development of novel therapeutics to treat bacterial infectio.

描述（由候选人提供）：由于抗生素耐药性的增加，细菌感染具有实质性的全球关注。金黄色葡萄球菌是一种警报的病原体，因为细菌几乎感染了人体中每个部位的能力。这种适应能力与抗生素耐药性的增加相结合导致与葡萄球菌感染相关的高水平发病率和死亡率。脊椎动物使用的强大策略战斗细菌病原体是必需营养物质的隔离，这是一种称为营养免疫的过程。最近的工作发现，在侵入性葡萄球菌疾病期间，成熟的脓肿实际上没有锰（MN）。进一步的工作表明，葡萄球菌感染期间MN的固相关取决于中性粒细胞蛋白钙粘蛋白（CP）S100A8和S100A9的异二聚体。在鼠类感染模型中，CP缺陷小鼠的葡萄球菌负担增加，表明金黄色葡萄球菌在感染过程中饿了。观察到在感染中抑制Mn依赖性细菌过程的观察结果进一步支持。总的来说，这些结果表明，CP会导致金黄色葡萄球菌在感染期间饥饿，而这种饥饿对于宿主防御至关重要。即使脊椎动物几乎没有MN，金黄色葡萄球菌仍然能够引起严重毁灭性的疾病。这些观察结果使我们假设金黄色葡萄球菌必须以某种方式适应宿主施加的MN限制。已知金黄色葡萄球菌表达专用的MN转运蛋白，这可能有助于该病原体抵抗脊椎动物金属隔离的作用。然而，CP缺陷小鼠中葡萄球菌毒力的增加表明，金黄色葡萄球菌对Mn转运蛋白的表达不足以防止金属饥饿。尽管众所周知，脊椎动物隔离Mn，但尚未阐明此过程的动力学，并且对金黄色葡萄球菌施加的Mn饥饿程度仍然未知。此外，金黄色葡萄球菌如何适应CP施加的MN饥饿也尚不清楚。该应用建议确定何时感染宿主隔离器Mn和金黄色葡萄球菌所经历的金属饥饿水平。此外，提出的实验将确定专用的MN进口系统对抵抗CP的贡献，并阐明金黄色葡萄球菌如何适应MN饥饿。本应用的具体目的如下：AIM 1。评估感染过程中MN固相的动力学以及金黄色葡萄球菌经历的MN缺乏程度。 AIM 2。确定MN进口系统是否有助于金黄色葡萄球菌克服脊椎动物MN固存的能力。目标3。确定金黄色链菌如何适应宿主施加的MN限制。公共卫生相关性：金黄色葡萄球菌等细菌病原体由于其实质性疾病负担和增加抗生素耐药性而引起人们的严重关注。为了打击这些入侵者，脊椎动物限制了必需营养素的可用性。这些研究将确定金黄色葡萄球菌用来克服宿主创建的营养限制环境的过程，从而促进了新型治疗剂以治疗细菌感染的过程。