Copper Homeostasis and virulence in Listeria monocytogenes

单核细胞增生李斯特菌是一种食源性细菌，可引起许多严重的人类感染。感染可能发生在未出生/新生婴儿身上，疾病可能表现为李斯特菌流产、死产或迟发性新生儿李斯特菌病。在成人中，感染通常影响中枢神经系统，引起脑膜炎。在美国，单核细胞增生乳杆菌占食源性感染死亡人数的28%，在癌症患者中，单核细胞增生乳杆菌是最常见的细菌性脑膜炎形式。本研究的目的是了解铜在单核增生乳杆菌中的稳态，并确定其在感染中的重要性。为了生存，细菌必须能够适应当地环境的变化并保持体内平衡。对铜等过渡元素水平变化的反应能力带来了一个难题。细菌必须平衡如何获得足够的铜，铜是某些酶的重要辅助因子，以及铜对细胞的毒性。在单核增生乳杆菌中，铜的体内平衡问题尤其严重。它生活在包括土壤、污水和食物在内的环境中，在那里它会暴露在波动的铜水平中。铜在动物饲料中用作抗微生物剂，在工厂化养殖中用作消毒剂，在水果生产中用作杀菌剂，这意味着单核细胞增多乳杆菌必须在食品生产和加工过程中与潜在有毒水平的铜作斗争。在感染期间，适应铜含量的波动很重要。单核增生乳杆菌在许多宿主组织中复制，这将对铜的可利用性提出不同的挑战。在感染早期，单核细胞增生乳杆菌生长在含有大量铜的胆囊中。相反，在肝脏和脾脏中，它在含有少量游离铜的环境中复制，在那里获得足够的铜是生长所必需的。在宿主内适应这些不同的生态位为成功感染提供了挑战。在改善人类健康方面，有许多潜在的好处。首先，了解铜在这一重要食源性病原体中的动态平衡将为当前食品生产中使用的铜基处理提供信息，并导致有效的减少单核增生乳杆菌污染的方案。其次，通过确定铜稳态在感染中的重要作用，从长远来看，有可能开发出基于铜稳态破坏的新型非抗生素治疗方法。

Listeria monocytogenes is a food borne bacterium that causes a number of serious infections in humans. Infection may be of the unborn/newly born infant where disease may manifest as listeric abortion, stillbirth or late-onset neonatal listeriosis. In adults, infection usually affects the central nervous system causing meningitis. In the USA L. monocytogenes accounts for 28% of all fatalities as a consequence of food borne infection and in cancer patients, L. monocytogenes is the most commonly encountered form of bacterial meningitis. The aims of this project are to understand copper homeostasis in L. monocytogenes and to establish its importance in infection.In order to survive bacteria have to be able to adapt to changes in their local environment and maintain homeostasis. The ability to respond to changes in the levels of transition elements such as copper provides a dilemma. Bacteria have to balance how to obtain sufficient copper, an essential cofactor for certain enzymes, with the toxicity of copper to the cell. In L. monocytogenes the problem of copper homeostasis is particularly acute. It inhabits environments including soil, effluents and food where it will be exposed to fluctuating copper levels. The use of copper as an anti-microbial in animal feeds, as a disinfectant in factory-based farming and as a biocide in fruit production means L. monocytogenes will have to combat potentially toxic levels of copper during food production and processing. Adapting to fluctuations in the level of copper is important during infections. L. monocytogenes replicates in a number of host tissues that will offer different challenges with regard to copper availability. Early in infection L. monocytogenes grows in the gall bladder, where there are high levels of copper. In contrast, in the liver and spleen it replicates in an environment containing little free copper and where the acquisition of sufficient copper for growth is essential. Adapting to these different niches within the host offers a challenge for a successful infection. In terms of improvements to human health, there are a number of potential benefits. First, an understanding copper homeostasis in this important food borne pathogen will inform the current copper based treatments used in food production and lead to effective regimes to reduce L. monocytogenes contamination. Secondly by establishing the essential role for copper homeostasis in infection it may be possible in the longer term to develop novel non-antibiotic based approaches for treatment of infections based on disruption of copper homeostasis.