New Plasmodium Strategies to Modulate Inflammation

调节炎症的新疟原虫策略

• 批准号: 7657970
• 负责人: ANA RODRIGUEZ
• 金额: $ 42.36万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657970
• 关键词: Acute; Adhesives; Affect; Allopurinol; Animals; Antigens; Biochemical; Blood; Brain; Cells; Cerebral Malaria; Cessation of life; Condition; Culture Media; Dendritic Cells; Development; Dinoprostone; Disease; Endothelial Cells; Enzymes; Erythrocytes; Fever; Fractionation; Generations; Gout; Human; Hypoxanthine; Hypoxanthines; Immune; Immune response; Immune system; In Vitro; Incubated; Infection; Inflammation; 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; extracellular; inhibitor/antagonist; macrophage; prevent; response; size; xanthine

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.

项目概要/摘要 疟原虫血期感染的特点是急性宿主炎症 高水平促炎细胞因子的反应，这有助于病理学 疾病。我们对约氏疟原虫的可溶性活性进行了分子表征 以及诱导小鼠释放前列腺素 E2、TNF 和 IL-6 的恶性疟原虫 树突状细胞。尺寸分级和质谱分析确定次黄嘌呤为 负责这些活动的分子。然而，我们观察到次黄嘌呤仅 当其降解为尿酸时具有活性。添加次黄嘌呤抑制剂别嘌呤醇 降解，抑制由约氏疟原虫感染的红细胞诱导的细胞因子的产生。 尿酸酶治疗还抑制树突状细胞分泌 TNF，这表明尿酸是 本次活动的最终调解人。尿酸是众所周知的免疫反应调节剂，因为它 痛风的病原体，已被确定为免疫系统的危险信号。 尿酸结晶对TNF的分泌具有激活或抑制的双重作用 根据条件，我们还发现了约氏疟原虫衍生的次黄嘌呤的双重作用 树突状细胞分泌的 TNF 的降解。我们还观察到治疗 别嘌呤醇导致受感染小鼠大脑中的 TNF 和 LT-α 增加以及 在其他不敏感的小鼠中产生脑型疟疾，表明次黄嘌呤 降解可预防小鼠脑型疟疾。我们还观察到 IL-12 增加，并且 这些小鼠脾脏中 IL-10 和 IL-6 的减少。 我们打算描述疟疾感染期间次黄嘌呤的降解，以及次黄嘌呤的作用。 产生的尿酸和活性氧，以及对先天性和适应性的影响 对疾病及其相关病理的免疫反应。作为细胞因子反应 疟疾影响先天免疫反应、T 细胞反应和 脑型疟疾的发生，我们将研究次黄嘌呤降解在这些疾病中的作用 小鼠疟疾感染过程。我们还将描述次黄嘌呤的作用 体外人类免疫细胞对恶性疟原虫反应的退化。 初步结果已表明该途径在 TNF 和 IL1beta 释放中发挥重要作用 响应恶性疟原虫感染的红细胞。 由于疟疾引起的炎症反应导致了大部分病理学 与疟疾感染（包括死亡）有关，了解这一点对于 开发有效的治疗方法。