Intracellular survival of Leishmania donovani demands rapid production of host ATP for its sustenance. However, gradual decrease in intracellular ATP in spite of increased glycolysis suggested ATP efflux during infection. Accordingly, extracellular ATP showed an increase and pannexin-1 was found to be the major ATP exporter in infected condition. Extracellular ATP also showed a gradual decrease after initial increase and analysing cell surface ATP-degrading enzymes revealed induction of the ectonucleotidases, CD39 and CD73. Ectonucleotidase mediated ATP degradation led to increased extracellular adenosine (eADO) and inhibiting CD39 and CD73 in infected cells decreased adenosine concentration and parasite survival, documenting importance of adenosine in infection. Inhibiting adenosine uptake by cells did not affect parasite survival implicating eADO might exert its effect through receptor-mediated signaling. Leishmania indeed induced expression of adenosine receptors A2AR and A2BR, both being important for anti-inflammatory responses. Treating infected BALB/c mice with CD39 and CD73 inhibitors resulted in decreased parasite burden and increased host-favourable cytokine production. Collectively, these observations indicate that infection-induced ATP is exported and after converting into adenosine exerts receptor-mediated signaling for propagating infection.

中文翻译：

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宿主 ATP 流出量的增加及其向细胞外腺苷的转化对于建立利什曼原虫感染至关重要。


杜氏利什曼原虫的细胞内生存需要宿主 ATP 的快速产生来维持其生存。然而，尽管糖酵解增加，但细胞内 ATP 逐渐减少，表明感染期间 ATP 外流。因此，细胞外 ATP 显示增加，并且发现 pannexin-1 是感染条件下的主要 ATP 输出者。细胞外 ATP 在最初增加后也显示出逐渐减少，并且分析细胞表面 ATP 降解酶揭示了核酸外切酶 CD39 和 CD73 的诱导。外核苷酸酶介导的 ATP 降解导致细胞外腺苷 (eADO) 增加，并抑制受感染细胞中的 CD39 和 CD73 降低腺苷浓度和寄生虫存活率，证明了腺苷在感染中的重要性。抑制细胞对腺苷的摄取并不影响寄生虫的存活，这表明 eADO 可能通过受体介导的信号传导发挥其作用。利什曼原虫确实诱导了腺苷受体 A2AR 和 A2BR 的表达，这两种受体对于抗炎反应都很重要。用 CD39 和 CD73 抑制剂治疗感染的 BALB/c 小鼠可减少寄生虫负担并增加宿主有利的细胞因子的产生。总的来说，这些观察结果表明，感染诱导的 ATP 被输出，并在转化为腺苷后发挥受体介导的信号传导以传播感染。