New Plasmodium Strategies to Modulate Inflammation

项目总结/摘要 疟原虫血液期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，这有助于病理的 疾病我们已经进行了约氏疟原虫可溶性活性的分子表征 和恶性疟原虫，其诱导小鼠释放前列腺素E2、TNF和IL-6 树突状细胞大小分级，然后质谱鉴定次黄嘌呤作为 分子负责这些活动。然而，我们观察到次黄嘌呤仅 当它被降解为尿酸时具有活性。添加别嘌呤醇，一种次黄嘌呤抑制剂 降解，抑制约氏疟原虫感染的红细胞诱导的细胞因子的产生。 尿酸酶处理也抑制了树突状细胞分泌TNF，这表明尿酸是树突状细胞分泌TNF的主要途径。 这一活动的最终调解人。尿酸是一种众所周知的免疫反应调节剂，因为它是 痛风的病原体，并已被确定为免疫系统的危险信号。 尿酸结晶对TNF的分泌具有双重作用，激活或抑制TNF的分泌。 根据不同的条件，我们还发现了约氏疟原虫衍生的次黄嘌呤的双重作用 通过树突状细胞对TNF分泌的降解。我们还观察到， 别嘌呤醇导致感染小鼠脑中TNF和LT-α的增加， 在其他非易感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的增加， 这些小鼠脾脏中IL-10和IL-6的减少。 我们打算描述次黄嘌呤在疟疾感染过程中的降解， 产生尿酸和活性氧，并在先天和适应性的影响， 对疾病及其相关病理的免疫应答。由于细胞因子对 疟疾影响先天免疫反应、T细胞反应和免疫应答的结果。 我们将研究次黄嘌呤降解在脑型疟疾中的作用， 在小鼠感染疟疾期间的过程。我们还将描述次黄嘌呤的作用， 在体外人免疫细胞对恶性疟原虫的应答中的降解。 初步结果已经显示该途径在TNF和IL 1 β释放中的重要作用 对恶性疟原虫感染红细胞的反应。 由于疟疾引起的炎症反应导致了大部分的病理变化， 与疟疾感染有关，包括死亡，了解它对预防疟疾至关重要。 开发有效的治疗方法。

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.