Manganese-iron interactions in the Lyme disease pathogen Borrelia burgdorferi

描述（由申请人提供）：莱姆病的伯氏疏螺旋体病原体是公共卫生中的一个持续问题。尽管有很强的免疫反应，但螺旋体可以在宿主体内持续存在，通常在很长一段时间内未被发现。一个聪明的改编是B。burgdorferi的能力，阻碍了强烈的铁饥饿反应的先天免疫。虽然大多数 病原体需要宿主铁来生存，B。Burgdorferi已经进化而不需要已知的铁，并且可以在没有可检测到的细胞铁的培养物中茁壮成长。Norgard及其同事发现，该病原体需要锰而不是铁来产生毒力。我们的研究计划长期专注于锰的生物学和细胞铁竞争池的影响。因此，B。burgdorferi是我们锰生理学比较研究的一个有趣的生物体。虽然大多数微生物积累微量水平的锰相比，细胞内的铁，B。burgdorferi能够积累非常高水平的锰而没有任何毒性迹象。尽管螺旋体对细胞内高锰有耐受性，但它不能耐受细胞外锰的微小增加。锰的这种有效抑制作用涉及锰与血清中的组分的相互作用，并且毒性与铁的摄取相关，而不是锰进入细胞。血清锰升高可增加铁的生物利用度并导致B生长抑制的机制。burgdorferi是这件事的焦点 提议通过候选分子和生化分离方法，我们试图分离负责B的血清因子。低锰对burgdorferi生长抑制和铁吸收的影响。我们还将研究铁的积累是否会干扰B中正常的金属-蛋白质伙伴关系。burgdorferi，包括选择的含锰酶。这项为期两年的独立研究将揭示锰-铁相互作用如何影响重要病原体的生理学。

DESCRIPTION (provided by applicant): The Borrelia burgdorferi pathogen for Lyme disease represents a continuing problem in public health. The spirochete can persist in a host in spite of a strong immune response, often undetected for extended periods. One clever adaption is B. burgdorferi's ability to thwart the intense iron starvation response of innate immunity. While most pathogens require host iron for survival, B. burgdorferi has evolved with no known requirement for iron and can thrive in culture without detectable cellular iron. Instead of iron, the pathogen requires manganese for virulence as shown by Norgard and colleagues. Our research program has a long-term focus on the biology of manganese and the effects of competing pools of cellular iron. As such, B. burgdorferi represented an intriguing organism for our comparative studies of manganese physiology. While most microorganisms accumulate trace levels of manganese compared to intracellular iron, B. burgdorferi is capable of accumulating extraordinarily high levels of manganese without any signs of toxicity. In spite of its tolerance t high intracellular manganese, the spirochete cannot tolerate even small increments in extracellular manganese. This potent inhibitory effect of manganese involves manganese interactions with a component in serum and toxicity correlates with uptake of iron, not manganese into the cell. The mechanism by which elevations in serum manganese can increase bioavailability of iron and cause growth inhibition of B. burgdorferi is the focus of this proposal. Through candidate molecule and biochemical fractionation approaches, we seek to isolate the serum factor(s) responsible for B. burgdorferi growth inhibition and iron uptake with low manganese. We will also investigate whether the iron accumulated interferes with normal metal-protein partnerships in B. burgdorferi, including select manganese containing enzymes. This self- contained two year study will shed new light into how manganese-iron interactions can affect the physiology of an important pathogen.