Adenosine pathway regulates inflammation during Plasmodium vivax infection

Abstract Background: Plasmodium spp. infection triggers the production of inflammatory cytokines that are essential for parasite control, and conversely responsible for symptoms of malaria. Monocytes play a role in host defense against Plasmodium vivax infection and represent the main source of inflammatory cytokines and reactive oxygen species. The anti-inflammatory cytokine IL-10 is a key regulator preventing exacerbated inflammatory responses. Studies suggested that different clinical presentations of malaria are strongly associated with an imbalance in the production of inflammatory and anti-inflammatory cytokines. Methods: A convenience sampling of peripheral blood mononuclear cells from Plasmodium vivax-infected patients and healthy donors were tested for the characterization of cytokine and adenosine production and the expression of ectonucleotidases and purinergic receptors. Results: Here we show that despite a strong inflammatory response, monocytes also bear a modulatory role during malaria. High levels of IL-10 are produced during P. vivax infection and its production can be triggered in monocytes by P. vivax-infected reticulocytes. Monocytes express high levels of ectonucleotidases, indicating their important role in extracellular ATP modulation and consequently in adenosine production. Plasmatic levels of adenosine are not altered in patients experiencing acute malaria; however, their monocyte subsets displayed an increased expression of P1 purinergic receptors. In addition, adenosine decreases Tumor Necrosis Factor production by monocytes, which was partially abolished with the blockage of the A2a receptor. Conclusion: Monocytes have a dual role, attempting to control both the P. vivax infection and the inflammatory response. Purinergic receptor modulators emerge as an untapped approach to ameliorate clinical malaria.背景：疟原虫属（Plasmodium spp.）感染可触发炎性细胞因子的产生，此类细胞因子既是寄生虫清除所必需的物质，同时也是疟疾临床症状的致病诱因。单核细胞在宿主抵御间日疟原虫（Plasmodium vivax）感染的过程中发挥关键作用，同时是炎性细胞因子与活性氧的主要来源。抗炎细胞因子白细胞介素10（IL-10）是防止过度炎症反应的核心调节因子。已有研究表明，疟疾的不同临床表型与炎性及抗炎细胞因子的产生失衡密切相关。 方法：本研究采用方便抽样法，采集间日疟原虫（Plasmodium vivax）感染患者与健康捐献者的外周血单个核细胞（peripheral blood mononuclear cells），对其细胞因子与腺苷的生成特征、胞外核苷酸酶（ectonucleotidases）及嘌呤能受体（purinergic receptors）的表达情况进行检测与表征分析。 结果：本研究结果显示，尽管间日疟原虫感染会引发强烈的炎症反应，单核细胞在疟疾病程中同时具备调节功能。感染期间可产生高水平的白细胞介素10（IL-10），而间日疟原虫感染的网织红细胞可诱导单核细胞产生该细胞因子。单核细胞高表达胞外核苷酸酶，表明其在细胞外ATP调控乃至腺苷生成过程中发挥重要作用。急性疟疾患者的血浆腺苷水平未出现明显改变，但患者的单核细胞亚群对P1嘌呤能受体的表达水平有所升高。此外，腺苷可降低单核细胞分泌肿瘤坏死因子（Tumor Necrosis Factor）的能力，该效应可通过A2a受体（A2a receptor）阻断得到部分抵消。 结论：单核细胞具备双重功能，既可辅助控制间日疟原虫感染，又能调节炎症反应。嘌呤能受体调节剂有望成为一种未被开发的疟疾临床改善手段。