Lipid signatures of West Nile virus infection unveil alterations of sphingolipid metabolism providing novel biomarkers

West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bites of infected mosquitoes. Severe forms of West Nile disease (WND) can curse with meningitis, encephalitis or acute flaccid paralysis. A better understanding of the physiopathology associated with disease progression is mandatory to find biomarkers and effective therapies. In this scenario, blood derivatives (plasma and serum) constitute the more commonly used biofluids due to its ease of collection and high value for diagnostic purposes. Therefore, the potential impact of this virus in the circulating lipidome was addressed combining the analysis of samples from experimentally infected mice and naturally WND patients. Our results unveil dynamic alterations in the lipidome that define specific metabolic fingerprints of different infection stages. Concomitant with neuroinvasion in mice, the lipid landscape was dominated by a metabolic reprograming that resulted in significant elevations of circulating sphingolipids (ceramides, dihydroceramides, and dihydrosphingomyelins), phosphatidylethanolamines and triacylglycerols. Remarkably, patients suffering from WND also displayed an elevation of ceramides, dihydroceramides, lactosylceramides, and monoacylglycerols in their sera. The dysregulation of sphingolipid metabolism by WNV may provide new therapeutic opportunities and supports the potential of certain lipids as novel peripheral biomarkers of WND progression.

西尼罗河病毒（West Nile virus, WNV）是一种经受感染蚊虫叮咬传播的嗜神经性黄病毒。西尼罗河病（West Nile disease, WND）的重症病例可表现为脑膜炎、脑炎或急性弛缓性麻痹。为发掘疾病进展相关的生物标志物并开发有效治疗手段，深入阐明与疾病进程相关的病理生理学机制是必要前提。在此背景下，血液衍生物（血浆与血清）因其采集便捷且在诊断领域具有较高应用价值，成为最常用的生物体液。为此，本研究结合实验感染小鼠样本与自然感染WND的患者样本进行分析，探究了该病毒对循环脂质组（circulating lipidome）的潜在影响。研究结果揭示了脂质组的动态变化，该变化可表征不同感染阶段的特异性代谢指纹谱。在小鼠出现神经侵袭的同时，其脂质谱以代谢重编程为主要特征，表现为循环鞘脂类（sphingolipids）、神经酰胺（ceramides）、二氢神经酰胺（dihydroceramides）、二氢鞘磷脂（dihydrosphingomyelins）、磷脂酰乙醇胺（phosphatidylethanolamines）及三酰甘油（triacylglycerols）水平显著升高。值得注意的是，WND患者的血清中同样出现了神经酰胺（ceramides）、二氢神经酰胺（dihydroceramides）、乳糖基神经酰胺（lactosylceramides）与单酰甘油（monoacylglycerols）水平升高的现象。WNV引发的鞘脂代谢紊乱或可为新型治疗策略提供思路，同时也支持部分脂质可作为WND疾病进程的新型外周生物标志物的潜在可能。