The impact of thermally-regulated cell wall modifications on Streptococcus pneumoniae pathogenesis

肺炎链球菌（SPN）是上呼吸道（鼻咽部）的天然定植菌，也是细菌性肺炎和严重侵袭性感染（包括败血症和脑膜炎）的主要原因。我们对无症状的鼻咽部感染发展为有症状疾病的过程只有部分了解，但人们早就知道呼吸道病毒感染与发生SPN肺炎的风险升高有关。可能导致这种关联的一个因素是宿主对病毒感染的反应对SPN的影响。发热时体温升高是由SPN检测到的，这种环境感知导致细菌的变化，这可能会促进它们引起疾病的能力。SPN能够对温度变化做出反应，部分原因是RNA热传感器的作用。这些调控元件阻止基因转录物被翻译成蛋白质。当温度升高时，RNA的结构变化消除了翻译的中断，蛋白质的生产可以恢复。只有少数SPN基因受这种温度调节机制的影响，其蛋白产物的产生与温度变化有关。热传感器已经在SPN基因中被描述，这些基因编码的蛋白质在病原体与宿主的相互作用中起重要作用。当温度升高时，会产生更多的这种蛋白质。我们已经在一个基因中发现了一个RNA热传感器，该基因编码一种修饰SPN细胞壁的蛋白质。SPN的进化研究表明，在同一途径上的基因可能在宿主组织的定植中起重要作用。细胞壁是病原体和宿主之间的重要界面，细胞壁结构的变化可能会促进或减轻SPN的毒力（致病潜力）。我们的目标是了解SPN细胞壁修饰的热调节是如何实现的，以及这对我们理解由这种病原体引起的疾病有什么意义。SPN在鼻咽部的天然栖息地（~33℃）比肺、血液或脑的疾病部位（37℃）要低，因此温度诱导的细胞壁变化可能有助于这些环境中的毒力。如果类似的变化是由发烧引起的，那么这可能部分解释了呼吸道病毒感染与SPN肺炎易感性的关联。了解温度在调节SPN毒力中的作用将有助于我们解释病毒感染与细菌性肺炎之间的联系，以及为什么SPN疾病的暴发发生在易受热浪和极端温度影响的地方。在未来，获得的信息将有助于鉴定适合作为疫苗靶点的SPN蛋白。我们将确定SPN细胞壁修饰酶CapD的产生是否受温度调节。我们将定义实现这种温度调节的机制，并探索细胞壁的修饰如何影响病原体和宿主之间的相互作用。使用感染模型，我们将确定细胞壁的热调节是否会影响感染结果，当SPN从鼻咽部转移到更温暖的肺部环境或当发烧使体温升高时，症状性疾病更有可能发生。

Streptococcus pneumoniae (SPN) is a natural coloniser of the upper airways (the nasopharynx) but also a major cause of bacterial pneumonia and serious invasive infections, including sepsis and meningitis. We only have partial understanding of the processes that cause asymptomatic nasopharyngeal infection to progress into symptomatic disease, but it has long been known that viral infections of the respiratory tract are associated with elevated risk of developing SPN pneumonia. One factor that might contribute to this association is the effect that the host response to viral infection has on SPN. The elevated body temperature during fever is detected by SPN and this environmental sensing leads to changes in the bacteria that might promote their ability to cause disease.SPN are able to respond to temperature changes, in part, due to the action of RNA thermosensors. These regulatory elements prevent gene transcripts from being translated into proteins. When the temperature rises, structural changes in the RNA removes this break on translation and protein production can resume. Only a small number of SPN genes are subject to this mechanism of thermoregulation, with the production of their protein products tied to temperature changes. Thermosensors have been described in SPN genes that encode proteins playing important roles in the interaction of pathogen with host. When the temperature rises, more of these proteins are produced. We have identified an RNA thermosensor in a gene encoding a protein that modifies the SPN cell wall. Evolutionary studies with SPN have suggested that genes in this same pathway might play important roles in colonisation of host tissues. The cell wall is an important interface between pathogen and host, and changes in cell wall structures may promote or lessen virulence (disease-causing potential) in SPN. We aim to understand how thermal regulation of cell wall modifications in SPN are achieved and what the implications are for our understanding of diseases caused by this pathogen. The natural home of SPN in the nasopharynx is cooler (~33C) than the disease sites of lung, blood or brain (37C), so temperature-induced changes in the cell wall may contribute to virulence in these environments. If similar changes are induced by fever, then this may partially explain the association of respiratory viral infection with susceptibility to SPN pneumonia. Understanding the role of temperature in modulating SPN virulence will help us explain the link between viral infection and bacterial pneumonia and why outbreaks of SPN disease occur in places subject to heatwaves and extremes of temperature. In the future, the information gained will help in identification of SPN proteins suitable as vaccine targets. We will determine whether the production of the SPN cell-wall modifying enzyme CapD is regulated by temperature. We will define the mechanism by which this thermoregulation is achieved and explore how the modifications to the cell wall influence the interactions between pathogen and host. Using infection models, we will determine whether thermal regulation of the cell wall influences infection outcomes, making symptomatic disease more likely when SPN moves from nasopharynx to the warmer environment of lungs or when fever raises the body temperature.