Sphingosine-1-phosphate and cryptococcosis

摘要 本项目的目的是研究宿主SK 1-S1 P通路在控制感染中的作用， 新生隐球菌（Cn）。在以前的研究中，我们确定了宿主鞘氨醇激酶1（SK 1）及其 产物鞘氨醇-1-磷酸（S1 P）对于针对Cn. 1 -3的肺肉芽肿的形成至关重要。 在小鼠中的研究得到以下观察结果的支持，即用FTY 720（芬戈莫德）治疗的患者的多个 当我们将FTY 720给予我们的小鼠肉芽肿模型时，Cn 肺部感染重新激活，真菌细胞从肺部扩散到脑组织，最终杀死了 动物有趣的是，用BAF 312或AUY 954处理未观察到这种效果。FTY 720是一种鞘氨醇， 类似物，一旦磷酸化，模拟S1 P并结合S1 P受体S1 Pr 1、S1 Pr 3和S1 Pr 510，而 BAF 312或AUY 954的未磷酸化形式分别结合S1 Pr 1和S1 Pr 5，11或仅结合S1 Pr 1，12。这些 结果表明，SK 1-S1 P可能通过调节肺肉芽肿中Cn细胞的容纳， 抑制特异性S1 P受体，如S1 Pr 3，因为这是FTY 720靶向的受体之一，但不是 其他化合物的影响。因为这些药物都通过阻断淋巴细胞的排出而引起严重的淋巴细胞减少症。 淋巴结淋巴细胞，13-15我们的研究还表明，淋巴细胞减少可能不足以引起Cn感染 重新激活 基于这些发现，我们假设S1 P对S1 Pr的作用调节宿主细胞的细胞增殖， 针对Cn和阻断S1 Pr 3免疫对宿主是有害的，并可导致 淋巴细胞减少症期间的隐球菌病。因此，我们将：1）确定SK 1-S1 P如何调节Cn的形成 肉芽肿;和2）定义由SK 1-S1 P控制的宿主免疫应答，其保护免受 Cn肉芽肿再活化。

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.