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Sphingosine-1-phosphate and cryptococcosis

1-磷酸鞘氨醇和隐球菌病

基本信息

批准号：
10338108
负责人：
Maurizio Del Poeta
金额：
$ 49.83万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-16 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338108
关键词：
Acquired Immunodeficiency Syndrome Address Age Animal Model Animals Binding Biological Response Modifiers Blood Brain CD4 Positive T Lymphocytes Cell Count Cells Cellular Immunity Containment Cryptococcosis Cryptococcus neoformans Cryptococcus neoformans infection Data Development Disease Goals Granuloma HIV Human Immune Immune response Immunity Immunocompetent Immunologic Deficiency Syndromes Immunosuppressive Agents Infection Inhalation Lead Lung Lung infections Lymphocyte Lymphopenia Malignant Neoplasms Meningoencephalitis Mus Mycoses Pathway interactions Patient observation Patients Phagocytes Pharmaceutical Preparations Primary Infection Reproduction spores Respiratory System Risk Role SPHK1 enzyme Signal Transduction Sphingosine Sphingosine-1-Phosphate Receptor T-Lymphocyte Therapeutic Validation Yeasts analog base brain tissue clinical development insight lymph nodes macrophage mouse model neutrophil novel therapeutic intervention pathogenic fungus pulmonary granuloma receptor recruit sphingosine 1-phosphate

项目摘要

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.

抽象的该项目的目标是研究宿主 SK1-S1P 通路在控制感染中的作用新型隐球菌（Cn）。在之前的研究中，我们发现宿主鞘氨醇激酶1（SK1）及其产品 1-磷酸鞘氨醇 (S1P) 对于针对 Cn.1-3 的肺肉芽肿的形成至关重要小鼠研究得到以下观察结果的支持：接受 FTY720（芬戈莫德）治疗的患者多次 sclerosis4 (MS) 发展为隐球菌病。5-9 当我们对小鼠肉芽肿模型施用 FTY720 时，Cn 肺部感染重新激活，真菌细胞从肺部传播到脑组织，最终杀死动物。有趣的是，BAF312 或 AUY954 治疗没有观察到这种效应。 FTY720 是一种鞘氨醇类似物，一旦磷酸化，就会模仿 S1P 并与 S1P 受体 S1Pr1、S1Pr3 和 S1Pr510 结合，而 BAF312 或 AUY954 的非磷酸化形式分别与 S1Pr1 和 S1Pr5,11 结合或仅与 S1Pr1,12 结合。这些结果表明 SK1-S1P 可能通过以下方式调节肺肉芽肿内 Cn 细胞的容纳：抑制特定 S1P 受体，例如 S1Pr3，因为这是 FTY720 靶向的受体之一，但不是由其他化合物。因为这些药物都通过阻止淋巴细胞的排出来诱发严重的淋巴细胞减少症。来自淋巴结的淋巴细胞，13-15 我们的研究还表明，淋巴细胞减少可能不足以导致 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针对 Cn 的免疫力，并且阻断 S1Pr3 对宿主有害，并可能导致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; 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。