Sphingosine-1-phosphate and cryptococcosis

摘要 本项目的目标是研究宿主SK1-S1P途径在控制感染中的作用。 新生隐球菌(CN)。在以前的研究中，我们发现宿主鞘氨醇激酶1(SK1)及其受体 产物鞘氨醇-1-磷酸(S1P)对Cn.1-3OUR肺肉芽肿的形成至关重要 在小鼠中的研究得到了以下观察的支持：患者使用FTY720(芬格莫特)治疗多发性 当我们给我们的小鼠肉芽肿模型CN注射FTY720时，菌核4(MS)发生了隐球菌病。 肺部感染重新激活，真菌细胞从肺扩散到脑组织，最终杀死 动物。有趣的是，BAF312或AUY954治疗没有观察到这种效果。FTY720是一种鞘氨醇 一种类似物，一旦磷酸化，模仿S1P并与S1P受体S1PR1、S1Pr3和S1Pr510结合，而 非磷酸化形式的BAF312或AUY954分别与S1PR1和S1Pr5，11结合或仅与S1Pr1，12结合。这些 结果提示，SK1-S1P可能通过调节肺肉芽肿内CN细胞的抑制而发挥作用。 抑制特定的S1P受体(S)，如S1Pr3，因为这是FTY720靶向的受体之一，但不是 其他化合物的作用。因为这些药物都通过阻断淋巴细胞的出口而导致严重的淋巴细胞减少。 来自淋巴结的淋巴细胞，13-15我们的研究还表明，淋巴减少可能不足以应对CN感染 重新激活。 基于这些发现，我们假设S1P对S1PR的作用调节宿主细胞 对CN和阻断S1Pr3的免疫对宿主有害，并可能导致重新激活 淋巴细胞减少期间的隐球菌病。因此，我们将：1)确定SK1-S1P如何调节CN的形成 肉芽肿；以及2)定义由SK1-S1P控制的宿主免疫反应，以防止 CN肉芽肿重新激活。

ABSTRACT The goal of this project is to study the role of the host SK1-S1P pathway in controlling the infection by Cryptococcus neoformans (Cn). In previous studies, we identified that the host sphingosine kinase 1 (SK1) and its product sphingosine-1-phosphate (S1P) are critical for the formation of the lung granuloma against Cn.1-3 Our studies in mice are supported by the observation that patients treated with FTY720 (Fingolimod) for multiple sclerosis4 (MS) developed cryptococcosis.5-9 When we administered FTY720 to our model of mouse granuloma, Cn lung infection reactivated and fungal cells disseminated from the lung to the brain tissue, eventually killing the animals. Intriguingly, this effect was not observed with BAF312 or AUY954 treatment. FTY720 is a sphingosine analog that, once phosphorylated, mimics S1P and binds to S1P receptors S1Pr1, S1Pr3 and S1Pr510 whereas the un-phosphorylated form of BAF312 or AUY954 binds to S1Pr1 and S1Pr5,11 or only to S1Pr1,12 respectively. These results suggest that SK1-S1P may regulate the containment of Cn cells within the lung granuloma through the inhibition of a specific S1P receptor(s), such as S1Pr3, as this is one of the receptors targeted by FTY720 but not by the other compounds. Because these drugs all induce a severe lymphopenia by blocking the egress of lymphocytes from lymph nodes,13-15 our studies also suggest that lymphopenia may not be sufficient for Cn infection to reactivate. Based on these findings, we hypothesize that the action of S1P on S1Pr regulates the host cellular immunity against Cn and that blocking S1Pr3 is detrimental for the host and may lead to reactivation of cryptococcosis during lymphopenia. Thus we will: 1) determine how SK1-S1P regulates the formation of Cn granuloma; and 2) define the host immune response controlled by SK1-S1P that protects against the reactivation of Cn granuloma.