Where and Why: The Influence of Host Metabolism on Bacterial Niche Specificity

这项工作的目的是确定细菌如何感知它们的环境是否适合殖民。在以前的工作中，我们已经表明，宿主代谢产物，D-丝氨酸，如果细菌结合到宿主组织的影响。目前的建议是重要的，因为如果这些传感机制可以被抑制，有机会开发新的方法来对抗病原体的干扰能力，占据特定的壁龛，从而防止发病。例如，我们的预测是，可以使用D-丝氨酸进行生长的菌株更有可能在这种氨基酸丰富的器官中引起感染，如尿路和大脑。对这种感染有强烈易感性的患者（例如导管患者，患有复发性膀胱感染的女性）的饮食可以进行调整，以降低尿液中这种氨基酸的浓度。这种通过饮食促进患者整体健康的做法完全符合BBSRC的战略重点“食品、营养和健康”。细菌在包括所有动物和植物在内的各种环境中生存和繁衍，既是微生物群最重要的组成部分，也是许多疾病的原因。细菌对健康和环境的贡献是巨大的，在免疫发育和营养循环等多种重要过程中发挥着核心作用。这些角色中的许多都需要细菌在一个特定的位置，一个特定的生态位上定居。因此，了解细菌如何以及为什么在特定地点定植是一个对健康，生物安全和食品生产具有深远影响的基本问题。我们的工作发现，一种不寻常的氨基酸，D-丝氨酸是由人类在某些组织中产生的。这种D-丝氨酸影响细菌对环境的反应，因此它可以促进或阻止殖民。换句话说，D-丝氨酸强烈地影响着在人体内特定小生境中定居的细菌。我们已经发现了集体感知和响应D-丝氨酸的蛋白质。令人着迷的是，一个核心蛋白，D-丝氨酸转运蛋白已被证明是自然界中最常见的序列之一。这突出了蛋白质对于更复杂的动物以及细菌的重要性。我们计划使用我们的细菌作为模型来帮助理解这个系统。我们想知道细菌如何检测这种氨基酸，因为它将有助于我们基本了解为什么会引起特定疾病。为了做到这一点，我们将使用多种方法的组合来剖析所涉及的分子途径。我们将研究氨基酸是如何结合的，以及它对结合它的蛋白质有什么影响，然后我们将研究这是如何导致影响细菌定植的因素的产生变化的。我们相信，我们的工作将为我们理解细菌如何引起特定疾病以及更广泛地说，它们如何与人类和其他动物宿主相互作用迈出重要一步。

The aim of this work is to determine to how bacteria sense if their environment is optimal for colonisation. In previous work we have shown that the host metabolite, D-serine, affects if bacteria bind to host tissues. The present proposal is important because if these sensing mechanisms can be inhibited, there is the opportunity to develop novel ways of combating pathogens by interfering with their ability to occupy specific niches, and therefore to prevent pathogenesis. For example, our prediction is that strains that can use D-serine for growth are more likely to cause infections in organs where this amino acid is abundant, such as the urinary tract and brain. The diet of patients with a strong susceptibility to such infections (e.g. patients with catheters, women with recurrent bladder infections) could be modified to reduce the concentration of this amino acid in their urine. This push towards overall patient health through diet perfectly fits the BBSRC strategic priority "Food, Nutrition and Health".Bacteria live and thrive in and on a huge variety of environments including all animals and plants, acting as both the most significant component of the microbiota and the cause of many diseases. The bacterial contribution to health and the environment is enormous with central roles in processes as diverse and important as immune development and nutrient cycling. Many of these roles require bacteria to colonise a defined location, a specific niche. Understanding how and why bacteria colonise particular sites is therefore a fundamental question with profound implications for health, biosecurity and food production. Our work has found that an unusual amino acid, D-serine is produced by humans in some tissues. This D-serine affects how bacteria respond to that environment, so it acts to either promote or discourage colonisation. In other words, D-serine strongly affects the bacteria that colonise particular niches within the human body.We have discovered the proteins that acts collectively to sense and respond to D-serine. Fascinatingly, one core protein, the D-serine transporter as been shown to be one of the most commonly found sequences in nature. This highlights just how important the protein in for more complex animals, as well as the bacteria. We plan to use our bacteria as a model to help understand this system. We want to know how bacteria detect this amino acid as it will help in our basic understand of why particular diseases are caused. To do this we will dissect the molecular pathway involved using a combination of methods. We will look at how the amino acid is bound and what effects it has on the proteins that bind it. We will then work out how this causes changes in the production of the factors that affect where and how the bacteria colonise. We are confident that our work will provide a major step forward in our understanding of how bacteria cause specific diseases and, more generally, how they interact with humans and other animal hosts.