New Plasmodium Strategies to Modulate Inflammation

调节炎症的新疟原虫策略

• 批准号: 7933271
• 负责人: ANA RODRIGUEZ
• 金额: $ 40.08万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933271
• 关键词: Acute; Adhesives; Affect; Allopurinol; Animals; Antigens; Biochemical; Blood; Brain; Cells; Cerebral Malaria; Cessation of life; Culture Media; Dendritic Cells; Development; Dinoprostone; Disease; Endothelial Cells; Enzymes; Erythrocytes; Fever; Fractionation; Generations; Gout; Human; Hypoxanthines; Immune; Immune response; Immune system; In Vitro; Incubated; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-12; Interleukin-6; Malaria; Mass Spectrum Analysis; Mediator of activation protein; Molecular; Mus; Organ; Outcome; Pathology; Pathway interactions; Plasmodium; Plasmodium falciparum; Process; Production; Reaction; Reactive Oxygen Species; Role; Signal Transduction; Spleen; Staging; T-Cell Activation; T-Lymphocyte; TNF gene; Tissues; Urate Oxidase; Uric Acid; Xanthine Dehydrogenase; Xanthines; abstracting; cell type; cytokine; effective therapy; extracellular; inhibitor/antagonist; macrophage; prevent; response

PROJECT SUMMARY/ABSTRACT Plasmodium blood-stage infection is characterized by an acute host inflammatory response with high levels of pro-inflammatory cytokines, which contribute to the pathology of the disease. We have performed the molecular characterization of a soluble activity from P. yoelii and P. falciparum that induces the release of prostaglandin E2, TNF and IL-6 from mouse dendritic cells. Size fractionation followed by mass spectrometry identified hypoxanthine as the molecule responsible for these activities. However, we observed that hypoxanthine was only active when it is degraded into uric. Addition of allopurinol, an inhibitor of hypoxanthine degradation, inhibited the production of cytokines induced by P. yoelii-infected erythrocytes. Also uricase treatment inhibited TNF secretion by dendritic cells, suggesting that uric acid is the final mediator of this activity. Uric acid is a well-known modulator of immune responses, as it is the causative agent of gout and has been identified as a danger signal for the immune system. Uric acid crystals can have a dual role on the secretion of TNF activating or inhibiting it depending on the conditions, we also found a dual role of P. yoelii-derived hypoxanthine degradation on TNF secretion by dendritic cells. We also observed that treatment with allopurinol results in increased TNF and LT-alpha in the brain of infected mice and in the generation of cerebral malaria in otherwise non-susceptible mice, suggesting that hypoxanthine degradation prevents cerebral malaria in mice. We also observed an increase in IL-12, and a decrease in IL-10 and IL-6 in spleens of these mice. We intend to characterize hypoxanthine degradation during malaria infections, the role of generated uric acid and reactive oxygen species, and the effects in the innate and adaptive immune response to the disease and its assoicated pathologies. As cytokine responses to malaria influence the outcome of innate immune responses, T cell responses and the generation of cerebral malaria, we will investigate the role of hypoxanthine degradation in these processes during malaria infections in mice. We will also characterize the role of hypoxanthine degradation in the response of human immune cells to Plasmodium falciparum in vitro. Preliminary Results already show a significant role of this pathway in TNF and IL1beta release in response to P. falciparum infected erythrocytes. As the malaria-induced inflammatory response contributes to most of the pathology associated with malaria infections, including death, its understanding is essential for the development of effective treatments.

项目摘要/摘要 疟原虫血液阶段感染的特征是急性宿主炎症 高水平的促炎细胞因子的反应，这有助于 疾病。我们已经进行了来自P. yoelii的可溶活性的分子表征 和恶性疟原虫，可诱导小鼠前列腺素E2，TNF和IL-6的释放 树突状细胞。尺寸分馏，然后质谱法确定了hyposoxanthine 负责这些活动的分子。但是，我们观察到半黄嘌呤仅是 当将其降解为尿液时活跃。添加别嘌呤醇，低黄嘌呤的抑制剂 降解，抑制了P. yoelii感染的红细胞诱导的细胞因子的产生。 尿酶处理也抑制树突状细胞的TNF分泌，表明尿酸是 这项活动的最终调解人。尿酸是免疫反应的众所周知的调节剂，因为它是 痛风的病因，已被确定为免疫系统的危险信号。 尿酸晶体可以在TNF激活或抑制它的分泌中具有双重作用 根据条件，我们还发现了叶叶疟原虫衍生的低黄嘌呤的双重作用 树突状细胞对TNF分泌的降解。我们还观察到了 异硫醇导致感染小鼠的大脑中的TNF和LT-Alpha增加 原本不敏感的小鼠中产生脑疟疾，表明低黄嘌呤 降解可防止小鼠的脑疟疾。我们还观察到IL-12的增加，A 这些小鼠脾脏中IL-10和IL-6的减少。 我们打算表征疟疾感染期间低黄嘌呤降解的作用 产生的尿酸和活性氧，以及先天和适应性的影响 对疾病及其辅助病理的免疫反应。作为细胞因子对 疟疾影响先天免疫反应，T细胞反应和 脑疟疾的产生，我们将研究低黄嘌呤降解在这些中的作用 小鼠疟疾感染过程中的过程。我们还将表征低黄嘌呤的作用 人类免疫细胞对恶性疟原虫在体外的反应中的降解。 初步结果已经显示出该途径在TNF和IL1BETA释放中的重要作用 响应恶性疟原虫感染的红细胞。 由于疟疾引起的炎症反应有助于大多数病理 与疟疾感染有关，包括死亡，其理解对于 开发有效的治疗方法。

项目成果

A surprising role for uric acid: the inflammatory malaria response.

• DOI: 10.1007/s11926-013-0401-8
• 发表时间: 2014-02
• 期刊: CURRENT RHEUMATOLOGY REPORTS
• 影响因子: 5
• 作者: Gallego-Delgado, Julio;Ty, Maureen;Orengo, Jamie M.;van de Hoef, Diana;Rodriguez, Ana
• 通讯作者: Rodriguez, Ana