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

• 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
• 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

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，细菌感染是全球关注的重大问题。金黄色葡萄球菌是一种值得警惕的病原体，因为这种细菌几乎能够感染人体的每一个部位。这种适应性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发病率和死亡率。脊椎动物利用这一有力的策略 对抗细菌病原体的关键是隔离必需营养素，这一过程被称为营养免疫。最近的研究发现，在侵袭性葡萄球菌疾病的成熟期，几乎没有锰（Mn）。进一步的研究表明，在葡萄球菌感染过程中锰的螯合依赖于中性粒细胞蛋白钙卫蛋白（CP）S100A8和S100A9的异二聚体。在小鼠感染模型中，CP缺陷小鼠的葡萄球菌负荷增加，表明S。金黄色葡萄球菌在感染期间是Mn饥饿的。这一观点进一步得到以下观察结果的支持：在感染期间，锰依赖性细菌过程受到抑制。总的来说，这些结果表明，CP导致S。金黄色葡萄球菌在感染期间变得Mn饥饿，并且这种饥饿对宿主防御至关重要。尽管脊椎动物创造了一个几乎没有锰、硫的环境。金黄色葡萄球菌仍然能够引起重大和毁灭性的疾病。这些观察使我们假设S。金黄色葡萄球菌必须以某种方式适应宿主施加的Mn限制。S.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螯合的作用。然而，CP缺陷小鼠中葡萄球菌毒力的增加表明，S.金黄色葡萄球菌不足以防止金属饥饿。尽管已知脊椎动物会吸收锰，但这一过程的动力学尚未阐明，也未阐明锰饥饿对S的影响程度。金黄色葡萄球菌仍然未知。此外，S.金黄色葡萄球菌适应CP施加的Mn饥饿也仍然不清楚。本申请提出确定在感染期间宿主何时隔离Mn和S所经历的金属饥饿水平。金黄色的此外，拟议的实验将确定专门的锰输入系统的贡献，以抵抗CP和阐明S。金黄色葡萄球菌适应锰饥饿。本申请的具体目的如下：目的1.评价感染过程中锰螯合的动力学和S.金黄色。目标二。确定Mn输入系统是否有助于S。金黄色葡萄球菌克服脊椎动物锰螯合。目标3.确定S。金黄色葡萄球菌适应由宿主施加的Mn限制。 公共卫生相关性：细菌病原体，如金黄色葡萄球菌，由于其巨大的疾病负担和不断增加的抗生素耐药性而受到严重关注。为了对抗这些入侵者，脊椎动物限制了必需营养素的可用性。这些研究将确定S.金黄色葡萄球菌用于克服宿主产生的营养限制环境，促进治疗细菌感染的新疗法的开发。