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.

项目总结/文摘