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

热调节细胞壁修饰对肺炎链球菌发病机制的影响

• 批准号: MR/X009130/1
• 负责人: Daniel Neill
• 金额: $ 66.17万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX009130%2F1
• 关键词: impact; thermally; regulated; cell; wall

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.

肺炎链球菌(SPN)是上呼吸道(鼻咽)的自然定植者，但也是细菌性肺炎和严重侵袭性感染的主要原因，包括败血症和脑膜炎。我们对导致无症状鼻咽感染进展为症状性疾病的过程只有部分了解，但很早就知道，呼吸道病毒感染与发展为SPN肺炎的风险增加有关。可能有助于这种联系的一个因素是宿主对病毒感染的反应对SPN的影响。发烧期间体温的升高是由SPN检测到的，这种环境感知会导致细菌的变化，这可能会促进它们致病的能力。SPN能够对温度变化做出反应，部分原因是RNA温度传感器的作用。这些调控元件阻止基因转录物转化为蛋白质。当温度上升时，RNA的结构变化消除了翻译上的这种中断，蛋白质的生产可以恢复。只有一小部分SPN基因受到这种体温调节机制的影响，其蛋白质产物的产生与温度变化有关。温度传感器已经在SPN基因中被描述，它编码的蛋白质在病原体与宿主的相互作用中起着重要的作用。当温度升高时，会产生更多这样的蛋白质。我们已经在编码修饰SPN细胞壁的蛋白质的基因中发现了一个RNA温度传感器。SPN的进化研究表明，同一途径中的基因可能在宿主组织的定植中发挥重要作用。细胞壁是病原菌和寄主之间的重要界面，细胞壁结构的变化可能会增强或减弱SPN的致病潜力。我们的目的是了解SPN中细胞壁修饰的热调节是如何实现的，以及这些调节对于我们理解这种病原体引起的疾病有什么意义。SPN在鼻咽的自然居所(~33℃)比肺、血或脑的发病部位(37℃)更冷，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肺炎易感性之间的联系。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和细菌性肺炎之间的联系，以及为什么SPN疾病的爆发发生在热浪和极端温度的地方。在未来，所获得的信息将有助于识别适合作为疫苗靶标的SPN蛋白。我们将确定SPN细胞壁修饰酶CAPD的产生是否受温度的调节。我们将定义实现这种体温调节的机制，并探索细胞壁的修改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影响感染结果，当SPN从鼻咽转移到较温暖的肺部环境或当发烧提高体温时，更有可能出现症状性疾病。