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

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令人警觉的病原体，因为这种细菌几乎可以感染人体的每一个部位。这种适应性加上不断增加的抗生素耐药性，导致了与葡萄球菌感染相关的高发病率和死亡率。脊椎动物利用的一种强大的策略 对抗细菌病原体是隔离必要的营养物质，这一过程被称为营养免疫。最近的研究发现，在侵袭性葡萄球菌病期间，成熟脓肿实际上缺乏锰(Mn)。进一步的研究表明，葡萄球菌感染过程中锰的隔离依赖于中性粒细胞蛋白钙保护素(CP)，它是S100A8和S100A9的异源二聚体。在小鼠感染模型中，CP缺乏的小鼠增加了金黄色葡萄球菌的负担，这表明金黄色葡萄球菌在感染期间缺乏锰。在感染期间，依赖锰的细菌过程受到抑制，这一观察进一步支持了这一观点。总之，这些结果表明，CP导致金黄色葡萄球菌在感染期间缺锰，这种饥饿对宿主防御至关重要。即使脊椎动物创造了一个几乎没有锰的环境，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门的锰转运体，这可能有助于该病原菌抵抗脊椎动物金属隔离的影响。然而，金黄色葡萄球菌在CP缺陷小鼠体内的毒力增加表明，金黄色葡萄球菌表达的锰转运蛋白不足以防止金属饥饿。虽然已经知道脊椎动物会隔离锰，但这一过程的动力学尚未阐明，造成金黄色葡萄球菌锰饥饿的程度也尚不清楚。此外，金黄色葡萄球菌如何适应CP施加的锰饥饿也尚不清楚。这项应用建议确定在感染期间宿主隔离锰的时间以及金黄色葡萄球菌经历的金属饥饿程度。此外，拟议的实验将确定专用的锰输入系统对抵抗CP的贡献，并阐明金黄色葡萄球菌如何适应锰饥饿。本研究的具体目的如下：目的1.评价金黄色葡萄球菌感染过程中锰的固存动力学和缺锰的程度。目的2.确定锰输入系统是否有助于金黄色葡萄球菌克服脊椎动物锰的固存。目的3.确定金黄色葡萄球菌对寄主施加的锰限制的适应情况。

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.