Section Experimental Virology, Institute of Medical Microbiology, University Hospital Jena, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, 07745, Jena, Germany.
Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC) and the Center for Molecular Biomedicine (CMB), University Hospital Jena, 07745, Jena, Germany.
Med Microbiol Immunol. 2018 Aug;207(3-4):227-242. doi: 10.1007/s00430-018-0543-4. Epub 2018 Apr 26.
The human cytomegalovirus (HCMV) is a common pathogen, which causes severe or even deadly diseases in immunocompromised patients. In addition, congenital HCMV infection represents a major health concern affecting especially the lung tissue of the susceptible individuals. Antivirals are a useful strategy to treat HCMV-caused diseases. However, all approved drugs target viral proteins but significant toxicity and an increasing resistance against these compounds have been observed. In infected cells, numerous host molecules have been identified to play important roles during HCMV replication. Among others, HCMV infection depends on the presence of bioactive sphingolipids. In this study, the role of sphingosine-1-phosphate (S1P) signaling in HCMV-infected human embryonal lung fibroblasts (HELF) was analyzed. Viral replication depended on the functional activity of sphingosine kinases (SK). During SK inhibition, addition of extracellular S1P restored HCMV replication. Moreover, neutralization of extracellular S1P by anti-S1P antibodies decreased HCMV replication as well. While the application of FTY720 as an functional antagonist of S1P receptor (S1PR) signaling did not reduce HCMV replication significantly, JTE-013, an inhibitor of S1PR, decreased viral replication. Furthermore, inhibition of Rac-1 activity reduced HCMV replication, whereas inhibition of the Rac-1 effector protein Rac-1-activated kinase 1 (PAK1) had no influence. In general, targeting S1P-induced pathways, which are essential for a successful HCMV replication, may represent a valuable strategy to develop new antiviral drugs.
人类巨细胞病毒（HCMV）是一种常见的病原体，可导致免疫功能低下的患者发生严重甚至致命的疾病。此外，先天性 HCMV 感染是一个主要的健康问题，尤其会影响易感个体的肺部组织。抗病毒药物是治疗 HCMV 引起的疾病的一种有效策略。然而，所有批准的药物都针对病毒蛋白，但已观察到这些化合物的显著毒性和耐药性增加。在受感染的细胞中，已经鉴定出许多宿主分子在 HCMV 复制过程中发挥重要作用。其中，HCMV 感染依赖于生物活性神经鞘氨醇 1-磷酸（S1P）信号的存在。在本研究中，分析了 S1P 信号在 HCMV 感染的人胚胎肺成纤维细胞（HELF）中的作用。病毒复制依赖于鞘氨醇激酶（SK）的功能活性。在 SK 抑制期间，添加细胞外 S1P 恢复了 HCMV 复制。此外，用抗 S1P 抗体中和细胞外 S1P 也降低了 HCMV 复制。虽然应用 FTY720 作为 S1P 受体（S1PR）信号的功能性拮抗剂并没有显著降低 HCMV 复制，但 S1PR 的抑制剂 JTE-013 降低了病毒复制。此外，抑制 Rac-1 活性降低了 HCMV 复制，而抑制 Rac-1 效应蛋白 Rac-1 激活激酶 1（PAK1）则没有影响。总的来说，针对 S1P 诱导的途径，这些途径对 HCMV 复制至关重要，可能是开发新抗病毒药物的有价值策略。
