Adenosine receptor-mediated effects of Clostridium difficile toxins in humans

腺苷受体介导的艰难梭菌毒素对人体的影响

• 批准号: 9177910
• 负责人: Cirle Alcantara Warren
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-21 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177910
• 关键词: Address; Adenosine; Adenosine A2B Receptor; Adenosine A3 Receptor; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Antibiotics; Apoptosis; Biology; Blood; Blood Circulation; Cell Death; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Clostridium difficile; Cyclic AMP; Data; Diarrhea; Disease; Disease Outbreaks; Enteral; Enterocytes; Epithelial; Epithelial Cells; G-Protein-Coupled Receptors; Human; Immune; Immune Cell Activation; Immune response; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Injury; Interferon Type II; Interleukin-6; Intervention; Intestines; Lead; Liquid substance; Mediating; Messenger RNA; Mus; Organism; Oryctolagus cuniculus; Pathogenesis; Pharmacology; Production; Purinergic P1 Receptors; Recurrence; Relapse; Research; Research Personnel; Resistance development; Sepsis; Signal Transduction; TNF gene; Therapeutic; Tissues; Toxin; Transcript; Treatment outcome; Virulence Factors; Water; Work; antimicrobial drug; cell type; collaborative environment; cytokine; disorder prevention; drug development; extracellular; gastrointestinal; improved; improved outcome; in vitro Model; innovation; insight; mortality; mouse model; neutrophil; novel; novel therapeutics; pathogen; receptor; response; rho; standard of care

PROJECT SUMMARY/ABSTRACT Clostridium difficile infection (CDI) is the single most common cause of infectious antibiotic-induced diarrhea. The primary virulence factors that are known to cause CDI are the two toxins: TcdA and TcdB. These toxins incite intense inflammation of the intestinal tissue and in severe cases, of the systemic circulation. Adenosine is released in increased amounts during tissue injury and its action is mediated by four receptors—A1, A2A, A2B and A3 adenosine receptors (AR). We have shown that TcdA and TcdB upregulate A2BAR and to lesser extent, A2AAR, transcript expression in a human intestinal cell line. Inhibition or deletion of A2BARs decreases TcdA-induced secretion and mucosal injury in ileal loops and in infected mice. While both A2AARs and A2BARs are known to be present in immune cells, gut epithelial cells express higher levels of A2BAR transcript than other cell types. We hypothesize that adenosine, through its interactions with A2BAR and A2AAR, modulates host responses to C. difficile toxins. Pharmacologic manipulation of these adenosine receptors will ameliorate toxin-induced epithelial injury and improve outcomes during infection. In this proposal, we shall determine how A2BAR inhibition regulates the local inflammatory responses to C. difficile toxins in primary human intestinal tissue (Aim 1). We shall also determine how A2AAR activation modulates systemic inflammatory responses to C. difficile toxins in human neutrophils (Aim 2). This research plan will provide insight into how A2AAR and A2BAR signaling mediate host immune responses to C. difficile toxins and how manipulation of these receptors may provide novel, non-antimicrobial, host-directed approaches to treating CDI.

项目摘要/摘要 艰难梭菌感染（CDI）是传染性抗生素引起的腹泻的最常见原因。 已知引起CDI的主要病毒因子是两种毒素：TCDA和TCDB。这些毒素 促进肠道组织的强烈炎症，在严重的情况下，全身循环。腺苷 在组织损伤期间释放量增加，其作用是由四个接收器介导的-A1，A2A，A2B 和A3腺苷受体（AR）。我们已经表明，TCDA和TCDB上调了A2BAR，并且较少 范围，A2AAR，在人肠细胞系中的转录本表达。抑制或删除A2BARS下降 TCDA诱导的回肠环和感染小鼠的分泌和粘膜损伤。而A2AAR和A2BARS则 已知存在于免疫细胞中，肠道上皮细胞表达的A2BAR转录水平高于 其他细胞类型。我们通过与A2BAR和A2AAR的相互作用来假设腺苷， 调节宿主对艰难梭菌毒素的反应。这些腺苷的药理操作 受体将改善毒素诱导的上皮损伤并改善感染期间的预后。在这个 提案，我们将确定A2BAR抑制如何调节对艰难梭菌的局部炎症反应 原代人肠组织中的毒素（AIM 1）。我们还将确定A2AAR激活如何调节 人类嗜中性粒细胞中对艰难梭菌毒素的全身性炎症反应（AIM 2）。该研究计划将 提供有关A2AAR和A2BAR信号如何介导宿主对艰难梭菌毒素的免疫反应以及 这些受体的操纵如何提供新颖的，非抗菌，宿主指导的方法 处理CDI。