Integration of nutrient availability, TCA cycle activity, and colonization factor expression in Campylobacter jejuni

空肠弯曲杆菌中营养利用率、TCA 循环活性和定植因子表达的整合

基本信息

  • 批准号:
    10661049
  • 负责人:
  • 金额:
    $ 36.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-06 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary Campylobacter jejuni is the leading cause of bacterial-derived gastroenteritis in the world. Human infection often occurs through the ingestion of contaminated food, especially poultry, which leads to the bacterium colonizing the colon and causing severe inflammation and diarrhea. While infection and disease is often self-limiting, persistent colonization and chronic diseases do occur. Despite the significant impacts of C. jejuni on human health, very little is known about the interactions that occur at the host-pathogen interface during infection, including how C. jejuni senses and adapts to the host intestinal environment to promote infection. This is primarily due to the evolutionary divergence of this organism from other gastrointestinal pathogens, which limits the relevance of findings from those organisms and necessitates specific study of the Campylobacter genus. To that end, our group previously identified a unique regulator in C. jejuni, which we call HeuR, that promotes maximum colonization of a natural avian host and was subsequently found to positively or negatively regulate several genetic determinants, including those involved in the acquisition of iron from host heme and the biosynthesis of methionine. In addition, HeuR and its downstream targets are required for efficient invasion or persistence in human colonocytes, which suggests these mechanisms need to be better understood as they are clearly involved in infection of animals. We preliminarily determined that this novel regulator binds several TCA intermediates and may sense TCA cycle activity to control expression of colonization determinants. First, we will define all direct targets of HeuR and examine whether TCA intermediates impact the ability of HeuR to bind those DNA targets and impact gene expression. Additionally, we will identify the ligand binding motif of this novel regulator and how it facilitates HeuR activity. Second, because we have determined that C. jejuni TCA intermediate abundance is affected by iron-restriction, we will use mass isotopomer analysis to identify the points along the C. jejuni TCA cycle that are affected by iron-limitation and determine whether altering TCA cycle activity affects HeuR-dependent colonization determinant expression. In addition, we will directly determine the levels at which each TCA enzyme indicated by mass isotopomer analysis is affected by iron-limitation. Lastly, one of the direct targets of HeuR we identified that may be impacted by TCA intermediate-dependent binding is the heme utilization system of C. jejuni. This system is poorly characterized in C. jejuni and we will examine whether this system facilitates iron acquisition during animal infection and will work to fully characterize the process of heme utilization so that it can be leveraged in future studies to inhibit the infection potential of C. jejuni.
项目摘要 空肠弯曲杆菌是世界上细菌性胃肠炎的主要病因。人类 感染通常是通过摄入受污染的食物,特别是家禽,从而导致 细菌在结肠中定植并引起严重的炎症和腹泻。而感染和疾病是 常常会发生自我限制、持久的殖民和慢性病。尽管C. 空肠病对人类健康的影响,对宿主-病原体界面上发生的相互作用知之甚少 感染,包括空肠弯曲菌如何感知和适应宿主肠道环境以促进感染。这 主要是由于这种微生物与其他胃肠道病原体在进化上的差异,这 限制了来自这些微生物的发现的相关性,并需要对弯曲杆菌进行专门的研究 属。为此,我们的团队之前在空肠弯曲菌中发现了一种独特的调节剂,我们称之为Heur, 促进自然禽类宿主的最大限度地定居,随后被发现积极或消极 调节几个遗传决定因素,包括那些涉及从宿主血红素中获取铁的决定因素和 蛋氨酸的生物合成。此外,Heur及其下游目标是有效入侵或 在人类结肠细胞中的持久性,这表明需要更好地了解这些机制 显然与感染动物有关。 我们初步确定这种新型的调节子可以结合几种三氯乙酸中间体,并可能感觉到 TCA循环活性以控制定植决定因素的表达。首先,我们将定义所有直接目标 Heur和检验TCA中间体是否影响Heur结合这些DNA靶标的能力并影响 基因表达。此外,我们将确定这种新型调节子的配体结合基序以及它如何促进 Heur活动。第二,因为我们已经确定空肠弯曲菌TCA的中间丰度受 铁限制,我们将使用质量同位素分析来确定沿空肠弯曲菌TCA循环的点是 受铁限制的影响,并确定改变TCA循环活性是否影响Heur依赖 定植决定基因的表达。此外,我们将直接确定每种TCA酶的水平 质量同分异构体分析表明,受铁限制的影响。最后,Heur WE的直接目标之一 确定可能受TCA中间依赖结合影响的是C。 空肠。这一系统在空肠弯曲菌中的特征很差,我们将检查这一系统是否有助于铁 在动物感染期间获得,并将致力于充分描述血红素利用的过程,以便它能够 在未来的研究中被用来抑制空肠弯曲菌的感染潜力。

项目成果

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